The document provides an overview of HIV protease inhibitors (PI), including:
1) PI are drugs that block the HIV protease enzyme, preventing maturation of viral particles.
2) Early PI were developed using structure-based drug design to create protease substrates that could bind irreversibly to the active site.
3) While PI treatment was a breakthrough, it can cause resistance and side effects, so future research focuses on new inhibitor classes and combination therapies.
This document reviews protease inhibitors, drugs used to treat AIDS. It discusses how HIV works by having the protease enzyme cleave viral polyproteins. Protease inhibitors were designed to bind to the protease and prevent this cleavage, stopping viral replication. Several protease inhibitor drugs are described, including lopinavir, ritonavir, and indinavir. While effective, protease inhibitors can cause side effects like increased blood sugar, changes in fat distribution, and liver problems. The summary concludes that protease inhibitors play an important role in regulating proteins and curing AIDS by binding HIV protease and preventing viral protein cleavage.
Relationship between hansch analysis and free wilson analysisKomalJAIN122
This document provides an overview of quantitative structure-activity relationship (QSAR) modeling techniques including Hansch analysis, Free-Wilson analysis, and Topliss schemes. It discusses how QSAR relates the biological activity of drugs to their physicochemical properties through equations. Specifically, it explains that Hansch equations relate activity to hydrophobicity, electronic effects, and steric factors. Examples of Hansch equations are provided. The Free-Wilson approach derives equations based on the presence or absence of substituents. Topliss schemes provide a methodical approach to substituent selection for optimization.
Molecular docking is a computer modeling technique used to predict the preferred orientation of one molecule to another when bound to form a stable complex. It involves fitting potential drug molecules into the active site of a protein receptor in order to identify which molecules may bind strongly. There are different approaches to molecular docking including rigid docking which treats molecules as rigid bodies, and flexible docking which accounts for conformational changes in ligands. The goal of docking is to find binding orientations that minimize the total energy of the system and maximize intermolecular interactions in order to predict effective drug candidates.
Rational drug design is a process that begins with knowledge of a biological target and aims to design small molecules that interact optimally with that target to produce a desired therapeutic effect. It involves analyzing the structures of active molecules and known targets, then designing new molecules that are predicted to specifically fit the target. This may involve modifying existing lead compounds or building new ones de novo. The goal is to develop drugs with greater potency, selectivity and fewer side effects than those found by traditional trial-and-error means. Cimetidine for reducing stomach acid is provided as an example of rational drug design, where histamine analogs were synthesized and optimized until an effective and safe product was obtained.
- β-Lactam antibiotics include penicillins, cephalosporins, carbapenems, and monobactams. They contain a β-lactam ring structure and inhibit bacterial cell wall synthesis.
- Penicillins were the first discovered from the mold Penicillium and include natural penicillin G as well as semi-synthetic derivatives like ampicillin. Cephalosporins were later derived from the fungus Cephalosporium and have greater gram-negative spectrum.
- Carbapenems like imipenem and meropenem have a very broad spectrum including Pseudomonas aeruginosa resistance to most β-lactamases. Monobactams such as aztre
This document reviews protease inhibitors, drugs used to treat AIDS. It discusses how HIV works by having the protease enzyme cleave viral polyproteins. Protease inhibitors were designed to bind to the protease and prevent this cleavage, stopping viral replication. Several protease inhibitor drugs are described, including lopinavir, ritonavir, and indinavir. While effective, protease inhibitors can cause side effects like increased blood sugar, changes in fat distribution, and liver problems. The summary concludes that protease inhibitors play an important role in regulating proteins and curing AIDS by binding HIV protease and preventing viral protein cleavage.
Relationship between hansch analysis and free wilson analysisKomalJAIN122
This document provides an overview of quantitative structure-activity relationship (QSAR) modeling techniques including Hansch analysis, Free-Wilson analysis, and Topliss schemes. It discusses how QSAR relates the biological activity of drugs to their physicochemical properties through equations. Specifically, it explains that Hansch equations relate activity to hydrophobicity, electronic effects, and steric factors. Examples of Hansch equations are provided. The Free-Wilson approach derives equations based on the presence or absence of substituents. Topliss schemes provide a methodical approach to substituent selection for optimization.
Molecular docking is a computer modeling technique used to predict the preferred orientation of one molecule to another when bound to form a stable complex. It involves fitting potential drug molecules into the active site of a protein receptor in order to identify which molecules may bind strongly. There are different approaches to molecular docking including rigid docking which treats molecules as rigid bodies, and flexible docking which accounts for conformational changes in ligands. The goal of docking is to find binding orientations that minimize the total energy of the system and maximize intermolecular interactions in order to predict effective drug candidates.
Rational drug design is a process that begins with knowledge of a biological target and aims to design small molecules that interact optimally with that target to produce a desired therapeutic effect. It involves analyzing the structures of active molecules and known targets, then designing new molecules that are predicted to specifically fit the target. This may involve modifying existing lead compounds or building new ones de novo. The goal is to develop drugs with greater potency, selectivity and fewer side effects than those found by traditional trial-and-error means. Cimetidine for reducing stomach acid is provided as an example of rational drug design, where histamine analogs were synthesized and optimized until an effective and safe product was obtained.
- β-Lactam antibiotics include penicillins, cephalosporins, carbapenems, and monobactams. They contain a β-lactam ring structure and inhibit bacterial cell wall synthesis.
- Penicillins were the first discovered from the mold Penicillium and include natural penicillin G as well as semi-synthetic derivatives like ampicillin. Cephalosporins were later derived from the fungus Cephalosporium and have greater gram-negative spectrum.
- Carbapenems like imipenem and meropenem have a very broad spectrum including Pseudomonas aeruginosa resistance to most β-lactamases. Monobactams such as aztre
PEPTIDOMIMETICS , HERE WE HAVE INCLUDED THE INTRODUCTION, CLASSIFICATION, ADVANTAGES , DISADVANTAGES, ITS METHODS PREPARATION, PRINCIPLES OD DRUG DESIGN, ITS CHEMISTRY. STEREOCHEMISTRY, SYNTHESIS AND APPLICATIONS
This document provides an overview of peptidomimetics. It begins with the evolution of peptidomimetics and how they were developed to overcome limitations of peptides as drugs. It then covers classification of peptidomimetics, design strategies like modifying amino acids and imposing structural constraints, and examples of peptidomimetic drugs that inhibit enzymes like ACE, thrombin, and HIV protease. The document concludes by stating peptidomimetics are an important area of drug design for developing small molecule mimics of peptide functions.
This document discusses combinatorial chemistry, which is a technique used to rapidly generate large libraries of compounds for screening and drug discovery. It defines combinatorial chemistry as producing large numbers of similar molecules using the same reaction conditions. The key principles are that it allows preparation of thousands of compounds per month using parallel synthesis techniques like solid and solution phase chemistry. This increases the chances of identifying hit compounds for pharmaceutical development compared to traditional synthetic methods. Applications of combinatorial chemistry include drug discovery, agrochemical and biotechnology research by creating molecular diversity libraries for high-throughput screening.
The document provides an overview of QSAR by Hansch analysis for predicting drug activity based on physicochemical properties. It discusses how graphs are used to correlate biological activity with properties like hydrophobicity, steric effects, and electronic effects. Regression analysis determines the correlation between activity and properties. Hansch equations combine multiple properties to predict activity. QSAR allows understanding relationships between structure and activity, aiding drug design by suggesting novel compounds. Limitations include need for property data and large sample sizes.
This document provides an introduction to Quantitative Structure Activity Relationships (QSAR) analysis using Hansch analysis. It discusses how QSAR attempts to correlate biological activity to measurable physicochemical properties of drugs using mathematical equations. It covers key topics like hydrophobicity, electronic effects, and steric effects of drug molecules and substituents. The document also explains the Hansch equation that relates biological activity to parameters like hydrophobicity (π), electronic effects (σ), and steric effects (Es). Examples of QSAR analyses and a table of common substituent parameters are also included.
The document discusses techniques for combinatorial synthesis, including solid phase techniques. Solid phase techniques involve attaching reactants to a polymeric surface to perform reactions. This allows excess reagents to be used and products to remain distinct and attached to beads. Linkers are used to attach reactants to resins and cleave final products. Common linkers include acid, amide, alcohol, and amine linkers. Solid supports include polystyrene, polyamide, and tentagel resins. Combinatorial synthesis techniques allow for parallel synthesis of multiple compounds.
Pharmacophore modeling identifies key molecular features necessary for drug-target binding and biological response. It represents molecules schematically in 2D or 3D. Pharmacophore features include hydrogen bond donors/acceptors, aromaticity, hydrophobicity and hydrophilicity. Pharmacophore models are used for virtual screening to identify molecules that may activate or inhibit a target. There are two main types: ligand-based models extract common features of known ligands, while structure-based models define features from protein-ligand complex structures. Both aim to encode the optimal 3D arrangement of interactions between ligands and targets.
QSAR attempts to find consistent relationships between biological activity and molecular properties using mathematical equations. Commonly studied molecular properties include lipophilicity, measured by log P values, and electronic effects, measured by Hammett constants. Hansch first applied QSAR by relating biological activity to log P and Hammett constants. Lipophilicity influences absorption and binding, while electronic effects impact reactivity. QSAR allows predicting new compounds' activities from prior data on similar molecules.
Combinatorial chemistry allows for the rapid synthesis of large libraries of compounds. It works by synthesizing many structures in parallel rather than one at a time. There are two main approaches: solid phase synthesis which attaches compounds to resin beads to isolate products, and solution phase which synthesizes in solvent. The libraries can be screened to identify active compounds more efficiently than traditional methods. This technique has increased the success of drug discovery by allowing testing of more structures at once.
This document discusses QSAR (quantitative structure-activity relationship), which is a mathematical model that relates biological activity to physicochemical properties of molecules. QSAR can be used to predict activity of new compounds. Key parameters used in QSAR include hydrophobicity (measured by partition coefficient), electronic effects (Hammett constant), and steric effects (Taft's steric factor). These parameters influence drug absorption, distribution, and interactions with receptors. QSAR models take the form of biological activity = function(parameters) to develop relationships between activity and molecular properties.
Combinatorial chemistry allows for the parallel synthesis and screening of large libraries of compounds. It involves combining sets of building blocks to generate many new molecules simultaneously. Techniques include solid and solution phase synthesis. Solid phase uses a solid support while solution phase lacks purification steps. Detection methods identify hits rapidly using hyphenated analytical techniques. Combinatorial chemistry has been applied to develop new drugs and agrochemicals by exploring vast areas of chemical space.
The Lipinski Rule of Five provides guidelines for drug-like properties that influence a compound's absorption and bioavailability after oral dosing. The rules specify that an orally active drug have less than 5 hydrogen bond donors, less than 10 hydrogen bond acceptors, a molecular weight less than 500, and an octanol-water partition coefficient log P of less than 5. Violating more than one of these guidelines reduces the likelihood of adequate absorption. While optimizing activity may increase violations by adding hydrogen bonds or lipophilicity, this can compromise a compound's drug-like properties.
Drug design and discovery is a complex, time-consuming and expensive process that involves identifying biological targets and developing ligands to interact with them. Computational tools and global gene expression analysis have increased efficiency by aiding in structure-guided drug design and target identification. The traditional methods of drug design involve developing ligands for targets with known structures or developing ligands with predefined properties for unknown targets. The drug development process takes an average of 10-15 years and has a high failure rate, with only a small fraction of potential drugs ultimately being approved after progressing through clinical trials and regulatory review.
The document discusses pharmacophores, which are abstract descriptions of molecular features necessary for molecular recognition between a ligand and biological macromolecule. A pharmacophore consists of 3D structural features like hydrophobic groups and hydrogen bond donors/acceptors. Pharmacophore mapping is used to define pharmacophoric features and align molecules to identify common binding elements responsible for biological activity. Pharmacophore models can be used in virtual screening to filter large databases and identify new compounds that may bind similarly to known active molecules. The document provides details on different approaches for pharmacophore generation and searching compound libraries.
The document discusses drug resistance in cancer therapy and antibiotic therapy. It provides causes and mechanisms of drug resistance, including alterations in drug targets, drug inactivation, reduced drug accumulation, and increased efflux pumps. Strategies to overcome resistance include pharmacokinetic monitoring, pharmacogenetic monitoring, and inhibiting efflux pumps. Drug resistance is a major challenge in cancer treatment and antibiotic use.
SAR versus QSAR, History and development of QSAR, Types of physicochemical
parameters, experimental and theoretical approaches for the determination of
physicochemical parameters such as Partition coefficient, Hammet’s substituent
constant and Taft’s steric constant. Hansch analysis, Free Wilson analysis, 3D-QSAR
approaches like COMFA and COMSIA.
Drug resistance occurs through several mechanisms: mutation, selective pressure, and gene transfer allow microbes to develop resistance. Strategies to combat resistance include international collaboration on surveillance and incentives for new drugs, national treatment guidelines and education programs, and community efforts like rational antibiotic use and hygiene. Genetic changes allow microbes to develop resistance through various mechanisms like mutation, selective pressure, and horizontal gene transfer between microbes.
Sythesis of heterocyclic drugs ketoconazole and metronidazoleandhra university
A Heterocyclic compounds are those which has atoms of at least two different elements as members of its ring.
Heterocyclic chemistry is a branch of organic chemistry dealing with the synthesis, properties, and applications of these heterocycles.
Spps and side reactions in peptide synthesiskavyakaparthi1
The document discusses side reactions that can occur during solid phase peptide synthesis (SPPS). It describes several types of side reactions including proton abstraction, racemization through azlactone formation or direct abstraction, cyclization through diketopiperazine formation, and O-acylation. Racemization is a particular concern in SPPS since it changes the stereochemistry of amino acids. The document outlines factors that influence the likelihood of different side reactions such as the amino acid, solvent, and presence of tertiary amines. Understanding side reactions is important for planning and carrying out efficient SPPS.
In this slide I covered the detailed about hansch analysis, Free-Wilson analysis, and Mixed approach. I also gave a detailed application for each points.
This document provides an overview of AIDS/HIV, including its etiology, pathogenesis, diagnosis, and treatment. It is caused by the HIV virus, which destroys CD4+ T cells. It is typically transmitted through bodily fluids. Diagnosis involves blood tests to detect HIV antibodies. Treatment involves antiretroviral drugs that target different stages of the viral lifecycle, such as reverse transcriptase inhibitors, protease inhibitors, and integrase inhibitors. Vaccine development has proven difficult due to HIV's ability to mutate and remain latent.
“Regulatory experience with monoclonal antibody submissions in the EU”
Provides an overview of the current EU assessment of biotherapeutics, focusing specifically on monoclonal antibodies
PEPTIDOMIMETICS , HERE WE HAVE INCLUDED THE INTRODUCTION, CLASSIFICATION, ADVANTAGES , DISADVANTAGES, ITS METHODS PREPARATION, PRINCIPLES OD DRUG DESIGN, ITS CHEMISTRY. STEREOCHEMISTRY, SYNTHESIS AND APPLICATIONS
This document provides an overview of peptidomimetics. It begins with the evolution of peptidomimetics and how they were developed to overcome limitations of peptides as drugs. It then covers classification of peptidomimetics, design strategies like modifying amino acids and imposing structural constraints, and examples of peptidomimetic drugs that inhibit enzymes like ACE, thrombin, and HIV protease. The document concludes by stating peptidomimetics are an important area of drug design for developing small molecule mimics of peptide functions.
This document discusses combinatorial chemistry, which is a technique used to rapidly generate large libraries of compounds for screening and drug discovery. It defines combinatorial chemistry as producing large numbers of similar molecules using the same reaction conditions. The key principles are that it allows preparation of thousands of compounds per month using parallel synthesis techniques like solid and solution phase chemistry. This increases the chances of identifying hit compounds for pharmaceutical development compared to traditional synthetic methods. Applications of combinatorial chemistry include drug discovery, agrochemical and biotechnology research by creating molecular diversity libraries for high-throughput screening.
The document provides an overview of QSAR by Hansch analysis for predicting drug activity based on physicochemical properties. It discusses how graphs are used to correlate biological activity with properties like hydrophobicity, steric effects, and electronic effects. Regression analysis determines the correlation between activity and properties. Hansch equations combine multiple properties to predict activity. QSAR allows understanding relationships between structure and activity, aiding drug design by suggesting novel compounds. Limitations include need for property data and large sample sizes.
This document provides an introduction to Quantitative Structure Activity Relationships (QSAR) analysis using Hansch analysis. It discusses how QSAR attempts to correlate biological activity to measurable physicochemical properties of drugs using mathematical equations. It covers key topics like hydrophobicity, electronic effects, and steric effects of drug molecules and substituents. The document also explains the Hansch equation that relates biological activity to parameters like hydrophobicity (π), electronic effects (σ), and steric effects (Es). Examples of QSAR analyses and a table of common substituent parameters are also included.
The document discusses techniques for combinatorial synthesis, including solid phase techniques. Solid phase techniques involve attaching reactants to a polymeric surface to perform reactions. This allows excess reagents to be used and products to remain distinct and attached to beads. Linkers are used to attach reactants to resins and cleave final products. Common linkers include acid, amide, alcohol, and amine linkers. Solid supports include polystyrene, polyamide, and tentagel resins. Combinatorial synthesis techniques allow for parallel synthesis of multiple compounds.
Pharmacophore modeling identifies key molecular features necessary for drug-target binding and biological response. It represents molecules schematically in 2D or 3D. Pharmacophore features include hydrogen bond donors/acceptors, aromaticity, hydrophobicity and hydrophilicity. Pharmacophore models are used for virtual screening to identify molecules that may activate or inhibit a target. There are two main types: ligand-based models extract common features of known ligands, while structure-based models define features from protein-ligand complex structures. Both aim to encode the optimal 3D arrangement of interactions between ligands and targets.
QSAR attempts to find consistent relationships between biological activity and molecular properties using mathematical equations. Commonly studied molecular properties include lipophilicity, measured by log P values, and electronic effects, measured by Hammett constants. Hansch first applied QSAR by relating biological activity to log P and Hammett constants. Lipophilicity influences absorption and binding, while electronic effects impact reactivity. QSAR allows predicting new compounds' activities from prior data on similar molecules.
Combinatorial chemistry allows for the rapid synthesis of large libraries of compounds. It works by synthesizing many structures in parallel rather than one at a time. There are two main approaches: solid phase synthesis which attaches compounds to resin beads to isolate products, and solution phase which synthesizes in solvent. The libraries can be screened to identify active compounds more efficiently than traditional methods. This technique has increased the success of drug discovery by allowing testing of more structures at once.
This document discusses QSAR (quantitative structure-activity relationship), which is a mathematical model that relates biological activity to physicochemical properties of molecules. QSAR can be used to predict activity of new compounds. Key parameters used in QSAR include hydrophobicity (measured by partition coefficient), electronic effects (Hammett constant), and steric effects (Taft's steric factor). These parameters influence drug absorption, distribution, and interactions with receptors. QSAR models take the form of biological activity = function(parameters) to develop relationships between activity and molecular properties.
Combinatorial chemistry allows for the parallel synthesis and screening of large libraries of compounds. It involves combining sets of building blocks to generate many new molecules simultaneously. Techniques include solid and solution phase synthesis. Solid phase uses a solid support while solution phase lacks purification steps. Detection methods identify hits rapidly using hyphenated analytical techniques. Combinatorial chemistry has been applied to develop new drugs and agrochemicals by exploring vast areas of chemical space.
The Lipinski Rule of Five provides guidelines for drug-like properties that influence a compound's absorption and bioavailability after oral dosing. The rules specify that an orally active drug have less than 5 hydrogen bond donors, less than 10 hydrogen bond acceptors, a molecular weight less than 500, and an octanol-water partition coefficient log P of less than 5. Violating more than one of these guidelines reduces the likelihood of adequate absorption. While optimizing activity may increase violations by adding hydrogen bonds or lipophilicity, this can compromise a compound's drug-like properties.
Drug design and discovery is a complex, time-consuming and expensive process that involves identifying biological targets and developing ligands to interact with them. Computational tools and global gene expression analysis have increased efficiency by aiding in structure-guided drug design and target identification. The traditional methods of drug design involve developing ligands for targets with known structures or developing ligands with predefined properties for unknown targets. The drug development process takes an average of 10-15 years and has a high failure rate, with only a small fraction of potential drugs ultimately being approved after progressing through clinical trials and regulatory review.
The document discusses pharmacophores, which are abstract descriptions of molecular features necessary for molecular recognition between a ligand and biological macromolecule. A pharmacophore consists of 3D structural features like hydrophobic groups and hydrogen bond donors/acceptors. Pharmacophore mapping is used to define pharmacophoric features and align molecules to identify common binding elements responsible for biological activity. Pharmacophore models can be used in virtual screening to filter large databases and identify new compounds that may bind similarly to known active molecules. The document provides details on different approaches for pharmacophore generation and searching compound libraries.
The document discusses drug resistance in cancer therapy and antibiotic therapy. It provides causes and mechanisms of drug resistance, including alterations in drug targets, drug inactivation, reduced drug accumulation, and increased efflux pumps. Strategies to overcome resistance include pharmacokinetic monitoring, pharmacogenetic monitoring, and inhibiting efflux pumps. Drug resistance is a major challenge in cancer treatment and antibiotic use.
SAR versus QSAR, History and development of QSAR, Types of physicochemical
parameters, experimental and theoretical approaches for the determination of
physicochemical parameters such as Partition coefficient, Hammet’s substituent
constant and Taft’s steric constant. Hansch analysis, Free Wilson analysis, 3D-QSAR
approaches like COMFA and COMSIA.
Drug resistance occurs through several mechanisms: mutation, selective pressure, and gene transfer allow microbes to develop resistance. Strategies to combat resistance include international collaboration on surveillance and incentives for new drugs, national treatment guidelines and education programs, and community efforts like rational antibiotic use and hygiene. Genetic changes allow microbes to develop resistance through various mechanisms like mutation, selective pressure, and horizontal gene transfer between microbes.
Sythesis of heterocyclic drugs ketoconazole and metronidazoleandhra university
A Heterocyclic compounds are those which has atoms of at least two different elements as members of its ring.
Heterocyclic chemistry is a branch of organic chemistry dealing with the synthesis, properties, and applications of these heterocycles.
Spps and side reactions in peptide synthesiskavyakaparthi1
The document discusses side reactions that can occur during solid phase peptide synthesis (SPPS). It describes several types of side reactions including proton abstraction, racemization through azlactone formation or direct abstraction, cyclization through diketopiperazine formation, and O-acylation. Racemization is a particular concern in SPPS since it changes the stereochemistry of amino acids. The document outlines factors that influence the likelihood of different side reactions such as the amino acid, solvent, and presence of tertiary amines. Understanding side reactions is important for planning and carrying out efficient SPPS.
In this slide I covered the detailed about hansch analysis, Free-Wilson analysis, and Mixed approach. I also gave a detailed application for each points.
This document provides an overview of AIDS/HIV, including its etiology, pathogenesis, diagnosis, and treatment. It is caused by the HIV virus, which destroys CD4+ T cells. It is typically transmitted through bodily fluids. Diagnosis involves blood tests to detect HIV antibodies. Treatment involves antiretroviral drugs that target different stages of the viral lifecycle, such as reverse transcriptase inhibitors, protease inhibitors, and integrase inhibitors. Vaccine development has proven difficult due to HIV's ability to mutate and remain latent.
“Regulatory experience with monoclonal antibody submissions in the EU”
Provides an overview of the current EU assessment of biotherapeutics, focusing specifically on monoclonal antibodies
This document discusses AIDS (Acquired Immunodeficiency Syndrome), which is caused by the HIV virus. It describes the structure and lifecycle of HIV, how it infects and damages immune cells, and its pathogenesis. The modes of transmission are explained. Diagnosis involves blood tests to detect HIV antibodies or RNA. Several classes of antiretroviral drugs are discussed that target different stages of the viral lifecycle, including reverse transcriptase inhibitors, protease inhibitors, fusion inhibitors, and integrase inhibitors. Recent drug developments target HIV entry and integration.
The document discusses the drug development process from pre-clinical research through Investigational New Drug (IND) application. It outlines the typical studies required to evaluate safety and toxicity, identify target organs of toxicity, determine appropriate dosing for clinical trials, and communicate risks. These include pharmacology, pharmacokinetics, safety pharmacology, acute and repeat-dose toxicology studies in two animal species along with genetic toxicology assays. The goals are to estimate initial safe doses for clinical trials and identify parameters that can monitor toxicity. The process seeks to identify potentially safe compounds for human testing while eliminating those that may be unsafe.
Biological agents are substances derived from living organisms that are used clinically for disease prevention, diagnosis, and treatment. This document discusses several types of biological agents including monoclonal antibodies, interleukins, interferons, and protein kinase inhibitors. It provides examples of specific drugs, describes their mechanisms of action and clinical applications. While biological agents demonstrate promising results in cancer treatment, their development and production is complex and costs are currently high compared to conventional chemotherapy.
Targeting Biological Aging: A New Paradigm for 21st Century MedicineInsideScientific
Biological age is the greatest risk factor for nearly every major cause of death and disability, including COVID-19. Yet, traditional biomedical research and clinical approaches have generally focused on waiting until people are sick and treating individual diseases one at a time. Attempts to cure age-related diseases have proven unsuccessful, and the impact of “disease-first” approaches continue to be incremental. Recent advances in understanding them mechanisms linking biological aging to disease, or geroscience, have identified interventions that directly target the molecular hallmarks of aging. Unlike disease-specific approaches, such interventions have the potential to prevent multiple diseases of aging simultaneously, thereby greatly enhancing healthspan and lifespan for most individuals.
During this webinar, Dr. Matt Kaeberlein will provide an overview of translational geroscience, which he believes will become the paradigm for the practice of medicine in the 21st century. He will also discuss recent work with one such intervention, the drug rapamycin, and its potential to enhance healthspan in companion dogs and people.
This document discusses the use of single nucleotide polymorphisms (SNPs) in pharmacogenomic studies. It begins by introducing personalized medicine and pharmacogenetics/pharmacogenomics. SNPs are described as the most common type of human genetic variation and are important in pharmacogenomic studies as they can affect drug metabolism and response. Methods for detecting SNPs like DNA sequencing and microarrays are presented. Examples are given of how SNPs in genes like TPMT, CYP2D6, and UGT1A1 can affect drug metabolism and dosing for medications like 6-mercaptopurine, codeine, and irinotecan. The SNP Consortium is summarized as a public effort to map SNPs to aid pharmacogen
Protective effects of n acetylcysteine on aluminum sukumar new 2222 (1)Sukumar Msuku
This study evaluated the protective effects of N-acetyl cysteine (NAC) on oxidative stress caused by aluminum phosphide poisoning. The study randomly assigned 37 patients with aluminum phosphide poisoning to either a treatment group that received NAC or a control group. Levels of malondialdehyde and total antioxidant capacity were measured at admission and 24 hours. The NAC group showed a significant decrease in malondialdehyde levels and no change in antioxidant levels, while the control group showed increased malondialdehyde and antioxidants. The NAC group also had lower rates of mechanical ventilation, shorter hospitalization, and lower mortality. The study concludes that NAC administration may help reduce oxidative stress and improve outcomes in aluminum phosphide poisoning.
This document provides information about the 9th annual conference on ADMET (Absorption, Distribution, Metabolism, Excretion and Toxicity) enhancing drug quality by ADMET optimisation in discovery that will take place from June 30th to July 2nd 2014 at the Marriott Regents Park Hotel in London. Key information includes:
- Discounts are available for booking by March 31st (save £300) and April 30th (save £100).
- The conference will focus on integrating ADMET and toxicity data to enhance drug safety prediction, drug transporters, predictive toxicology, and computational/in vitro ADMET approaches.
- There will be presentations from industry leaders at companies like
HIV/ AIDs Slide reviewing insights about these type of RTA .pptxkwartengprince250
The document defines HIV and AIDS, describing HIV as a virus that attacks immune cells and AIDS as the late stage of HIV infection when the immune system is severely damaged. It provides details on the epidemiology of HIV/AIDS globally and in Ghana, the types and structure of HIV, how it is transmitted, the stages and symptoms of HIV infection, diagnostic tests including viral load and CD4 counts, opportunistic infections associated with AIDS, antiretroviral treatment regimens, and prevention of HIV transmission.
Healthcare Professional financial guide to partnership with Pharmenex Biopho...Ching Chen
- Pharmanex was co-founded in 1996 to bring quality control and standards to the nutritional industry after the founder spent 15 years in the pharmaceutical industry.
- It achieved $50 million in annual sales and was purchased by Nu Skin Enterprises in 1998 for $135 million.
- Nu Skin's anti-aging research and development team includes over 75 PhD-level scientists researching botanicals and developing products.
- The company has a world-class scientific advisory board of pioneers in various fields related to health, aging, and nutrition.
HIV screening and treatment in as changes occur in our healthcare system. Targeted towards specific healthcare centers in Baltimore. Features some data from the Department of health and mental hygiene and new data on HIV transmission across continuum of HIV care.
This document describes a collaboration between Findacure, a UK charity focused on rare diseases, and Elsevier to mobilize informational resources for congenital hyperinsulinism (CHI), a rare genetic disease. Elsevier will provide Findacure access to its extensive literature database and text mining capabilities to summarize what is known about CHI mechanisms, identify potential drug targets, and find approved drugs that may treat CHI. The collaboration aims to support Findacure's efforts to drive research, develop treatments, and help patients by providing structured, analyzed information extracted from Elsevier's literature and linking researchers and institutions working on CHI.
Manipal Hospitals Brookefield clinic is the best multi-specialty clinic in Brookfield Bangalore near Whitefield, providing world-class healthcare services with top doctors.Visit us at: https://www.manipalhospitals.com/clinics-brookefield/
INDIGENOUS AYURVEDIC HERBALS AND SUPPLEMENTS – ARE THEY REALLY SAFE?KatySam
Manipal Hospitals Brookefield clinic is the best multi-specialty clinic in Brookfield Bangalore near Whitefield, providing world-class healthcare services with top doctors.Visit us at: https://www.manipalhospitals.com/clinics-brookefield/
This document discusses the rationale for using whole blood for trauma resuscitation. It describes the THOR Network, an international collaborative focused on improving outcomes from traumatic hemorrhagic shock. The network aims to develop and implement best practices for prehospital care through completion of acute resuscitation. Low titer group O whole blood is described as optimal for trauma-induced blood failure compared to blood components. Data is presented showing whole blood provides higher concentrations of red blood cells, platelets, and coagulation factors in a smaller volume than separated components. Future directions discussed include developing artificial red blood cells and dried plasma.
1) The document discusses factors that can affect in vitro fertilization (IVF) success rates, based on an evidence-based review with chapters written by experts.
2) Patient preparation prior to IVF treatment is important and includes hormonal and ultrasound screening, surgery if needed, vitamin/nutrient supplementation, weight control, and testing for thrombophilia and immunological factors.
3) Stimulation regimens, monitoring during treatment, laboratory aspects like culture media and embryo selection techniques, embryo transfer methodology, and ancillary treatments are also factors that can impact IVF success rates.
This document summarizes factors that can affect in vitro fertilization (IVF) success rates based on an evidence-based review. It discusses patient preparation including hormonal and ultrasound screening, surgery for fibroids or endometriosis, vitamin supplementation, weight control, and screening for thrombophilia and immunological factors. It also discusses stimulation regimens, monitoring approaches, laboratory aspects such as sperm preparation and embryo culture conditions, embryo selection techniques, embryo transfer procedures, and ancillary treatments though some treatments like immunotherapy have no conclusive evidence of benefit. The overall goal is to optimize each step of the IVF process based on the best available evidence to improve pregnancy and live birth rates.
This document provides an overview of various pathogen inactivation methods for blood components including plasma, platelets, red blood cells, and whole blood. It discusses both chemical and physical methods such as solvent-detergent treatment, methylene blue with light activation, amotosalen with UVA light, and riboflavin with UV light. The document outlines the mechanisms of action of these different methods and their effectiveness against various pathogens including viruses, bacteria, and parasites. It also notes some of the limitations of current pathogen inactivation technologies, such as potential damage to blood components and residual infectivity of some non-enveloped viruses.
2. • Brief overview of HIV/AIDS
• Very brief structure, entry, replication cycle, genome
• HIV Protease (HIV PR)
• Protease Inhibitors (PI)
• Development of PI
• Downsides of PI treatments
• Future of PI
OUTLINE
3. • Acquired immunodeficiency syndrome
(AIDS)
• Estimated 25 million people have died as a
result of AIDS
• AIDS is typically diagnosed 7-8 years after
initial infection
• Immune system has been fully
compromised
• Death is usually the result of an
opportunistic infection
• Human Immunodeficiency Virus 1 (HIV-1) is a
retrovirus and the primary cause of Acquired
immunodeficiency syndrome (AIDS)
• Origin
– SIVcpz
• Mode of Transmission:
– Blood
– Semen
– Vaginal fluids
– Breast milk
• Main target:
– CD4 lymphocyte
• Stages of HIV infection
– Acute
– Clinical
– AIDS
HIV/AIDS
4. • 1994 – AIDS becomes #1 CoD for
Americans age 25-44
• June 1, 1995 – FDA approves P.I.
and HAART
• 1995 – AIDS in US reaches 500,000
• 1997 – P.I. treatment causes viral
resistance increase
• 2000 – President Clinton declares
HIV/AIDS a threat to national
security
• June 5, 1981 – First reports of
immunocompromised gay men
• February 1, 1983 – Dr. Robert Gallo
suggests the retrovirus is
responsible
• January 1, 1985 – FDA approves
ELISA to detect HIVab
• January 11, 1985 – CDC reports
AIDS is caused by a “new” virus
• 1989 – AIDS in US reaches 100,000
TIMELINE OF HIV/AIDS
11. • Primary function: cleave long
polypeptides from translated gag and
pol genes.
• Inhibition of HIV protease results in the
release of immature and noninfectious
viral particles.
• Structure and function similar to
human renin and pepsin
• **Warning: Organic Chemistry Ahead**
HIV PR
Adamson, Catherine S. 2012
12. • C2 symmetric, 198-amino acid
homodimeric aspartyl protease
• Active site consists of two conserved
aspartic acid residues
– Asp-Thr-Gly motif
• Semi-open conformation
– Two models of activation
• Why is this important?
HIV PR
Credit: David R. Davies. The Structure and Function of Aspartic Proteinases. (1990)
13. HIV PR MECHANISM OF ACTION
http://upload.wikimedia.org/wikipedia/commons/0/00/Aspartyl_protease_mechanism.png
Nucleophilic Addition-Elimination Reaction
15. How do we
stop this?
https://www.youtube.com/watch?v=RO8MP3wMvqg
16. • Protease inhibitors are drugs that block a protease from making active
proteins
• Competitive inhibition
• Discovered primarily through structure-based drug design and a LOT of
organic/protein chemistry
• Goals
– Suppress viral load
– Reduce morbidity
– Maximize survival
– Restore and maintain immunological function
PROTEASE INHIBITORS (P.I.)
17. Protease Inhibitor
(1st Generation)
Dosage Structure
Saquinivir (1995)
Inverase
(Roche Labs)
SQV/r 1800mg/200mg
(600mg 3x/d)
With fatty meals
Ritonavir (1996)**
Norvir
(Abbott Labs)
2400mg/daily
(100, 200, 400mg 3x/d)
With or without food
Indinavir (1996)
Crixivan
(Merck)
IDV/r + EFV: 800mg every 8h
(100, 200, 400mg capsule)
Empty stomach
Nelfinavir (1997)
Viracept
(Agouron)
2,250mg/daily
(750mg 3x/d or 1250 2x/d)
With meals
19. • The development of P.I. involved a lot of organic chemistry, biochemistry
and, new at the time, protein crystallography and computer chemistry
• Structure-based and substrate-based
DEVELOPMENT OF PI
20. • The five first generation protease inhibitors were based on renin and
pepsin inhibitors (pepstatin)
• The idea was to create a substrate that can bind the active site as an
analogue, but be uncleavable.
DEVELOPMENT OF PI
Virlgil, Scott C. “First Generation HIV-1 Protease Inhibitors for the Treatment of HIV/AIDS”. 2010.
23. • The inhibitors are analogues of
the substrates that PR would
normally recognize.
• Peptidomimetic transition-state
analogues
• Normal peptide linkage
– [—NH—CO—]
• Inhibitor linkage
– [—CH2—CH(OH)—]
P.I. MECHANISM OF ACTION
Lead Compound
Asp25---Asp125
X
25. • Monotherapy
– Protease inhibitor on it’s own (downsides)
• Combination Therapy
– 2 Protease inhibitors (boosted PI)
• ATV/r
– PI + NRTI, PI + NNRTI, PI + I.I., PI + BI
• HAART
– Combination therapy of PI + RTI + II
– Usually the most effective method of treatment
P.I. APPLICATIONS IN THERAPY
26. • Increased viral resistance
• Creation of new protease enzymes via integrase
• Expensive
• Time
• Drug Interactions
• Side effects
• Patient Compliance
• Genetic Polymorphisms
DOWNSIDES AND CHALLENGES
27. • Allosteric inhibitors
• The challenge will be to combat resistance
• Maturation Inhibitors – block the specific proteolytic processing of Gag
and Gag-Pol genes
– Bevirimat (BVM)
• 3-O-(3’,3’-dimethylsuccinyl) betulinic acid
• HIV-2 and SIV are not sensitive to BVM
– PF-46396
• 1-[2-(4-tert-butylphenyl)-2-(2,3-dihydro-1H-inden-2-ylamino)ethyl]-3-(trifluoromethyl)pyridin-2-one
• Still in trial phase, but promising
FUTURE OF PROTEASE INHIBITORS
28. • Acheson, Nicholas H. Fundamentals of Molecular Virology. 2nd ed. New Jersey: John Wiley & Sons, Inc, 2011. Print.
• Adamson, Catherine S. (2012). “Protease-Mediated Maturation of HIV: Inhibitors of Protease and the Maturation
Process.” Molecular Biology International 2012: 1-13.
http://scholar.google.com/scholar_url?url=http://downloads.hindawi.com/journals/mbi/2012/604261.pdf&hl=en&sa
=X&scisig=AAGBfm0kCsPPdYS6976mi6S1AhBRIQOO6Q&nossl=1&oi=scholarr
• Ali, Akbar et al. (2010). “Molecular Basis for Drug Resistance in HIV-1 Protease.” Viruses 2: 2509-2525.
http://scholar.google.com/scholar_url?url=http://www.mdpi.com/1999-
4915/2/11/2509/pdf&hl=en&sa=X&scisig=AAGBfm09kKIsQJtvP9i_iTPP-1GpgW16zA&nossl=1&oi=scholarr
• Cruciani, Mario. (2014). “Virological efficacy of abacavir: systematic review and meta-analysis.” Journal of
Antimicrobial Chemotherapy 69: 3169-3180. http://jac.oxfordjournals.org/content/69/12/3169.full.pdf+html
• Davies, David R. (1990). “The Structure and Function of the Aspartic Proteases.” Annual Review of Biophysics and
Biophysical Chemistry 19: 189-215. http://www.annualreviews.org/doi/abs/10.1146/annurev.bb.19.060190.001201
• Eron Jr., Joseph J. (2000). “HIV-1 Protease Inhibitors.” Infectious Diseases Society of America 30: S160-170.
http://cid.oxfordjournals.org/content/30/Supplement_2/S160.short
• Gaczynska, M., Osmulski, P.A. (2014). “Harnessing Proteasome Dynamics and Allostery in Drug Design.” Antioxidants
& Redox Signaling 21.17: 2286-2297. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4241894/
BIBLIOGRAPHY
29. • Hughes, Peter J. et al. (2011). “Protease Inhibitors for Patients with HIV-1 infection: A Comparative Overview.”
Pharmacy and Therapeutics 36.6: 332-343. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3138376/
• Lefebvre, Eric., Schiffer, Celia A. (2008). “Resilience to Resistance of HIV-1 Protease Inhibitors: Profile of Darunavir.”
AIDS Review 10: 131-142. http://www.ncbi.nlm.nih.gov/pubmed/18820715
• Ogden, Richard C., Flexner, Charles W. Protease Inhibitors in AIDS Therapy. New York: Marcel Dekker, Inc., 2007. Print.
• Sharp, Paul M., Hahn, Beatrice H. (2011). “Origins of HIV and the AIDS Pandemic.” Cold Spring Harbor Perspectives in
Medicine 1: 1-16. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3234451/
• Virgil, Scott C. (2010). “First-Generation HIV-1 Protease Inhibitors for the Treatment of HIV/AIDS.” Aspartic Acid
Proteases as Therapeutic Targets. 139-161. http://onlinelibrary.wiley.com/doi/10.1002/9783527630943.ch6/pdf
• Yang, Hailiu et al. (2012). “Effects of HIV-1 Protease on Cellular Functions and their Potential Applications in
Antiretroviral Therapy.” Cell & Bioscience 2.32: 1-8. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3490751/
• “What is HIV/AIDS?” AIDS.gov. 29 April, 2014. Web. Accessed 30 March, 2015 from https://www.aids.gov/hiv-aids-
basics/
BIBLIOGRAPHY
30. • “Protease Inhibitors.” AIDSmap. 2015. Web. Accessed 1 April, 2015 from
http://www.aidsmap.com/Protease-inhibitors/page/1729414/
• “HIV Protease.” YouTube. Uploaded 12 May, 2007. Web. Accessed 1 April, 2015 from
https://www.youtube.com/watch?v=UvElXNo_aPw
• “HIV Replication 3D Medical Animation.” YouTube. Uploaded 3 March, 2007. Web. Accessed 1
April, 2015 from https://www.youtube.com/watch?v=RO8MP3wMvqg“Stages of HIV Infection.”
AIDS.gov. 19 December, 2013. Web. Accessed 2 April, 2015 from https://www.aids.gov/hiv-aids-
basics/just-diagnosed-with-hiv-aids/hiv-in-your-body/stages-of-hiv/index.html
• “Retroviral Proteases.” Retroviral Proteases. N.d. Web. Accessed 2 April, 2015 from
http://www.cs.stedwards.edu/chem/Chemistry/CHEM43/CHEM43/RetroV/BiochemProject.html
• “Aspartic Protease Inhibitors.” Cambridge MedChem Consulting. 2012. Web. Accessed 6 April,
2015 from
http://www.cambridgemedchemconsulting.com/resources/hit_identification/aspartic_protease_in
hibitors.html
BIBLIOGRAPHY
Origin – HIV-1 was sequenced to SIV and found that they are similar. It has been determined that HIV-1 is a zoonotic infection likely transmitted in the early 1900s (there were reports in the 1900s of healthy individuals succumbing to opportunistic infections) from butchered chimpanzees infected with SIVcpz. Monkeys do not, however, succumb to the same clinical syndromes seen in humans infected with HIV-1. This suggests an adaptation through selection
Mode of Transmission – the virus enters the body through those listed modes through mucocutaneous areas that line the mouth, vagina, rectum, penis and upper GI tract
June 5, 1981 – marked depletion of CD4+ T-lymphocytes of otherwise healthy young men in Los Angeles/San Francisco.
Binding and fusion – HIV binds to a CD4 receptor and coreceptor on the surface of the cell. The glycoproteins involved are GP120 and GP41. GP 120 binds to CD4 and attaches. This will allow GP41 to fold out and insert its hydrophobic tip into the cell membrane. GP41 then folds over itself to bring the virus and cell together where they fuse and viral genetic material is released.
Reverse Transcription – Reverse transcriptase is one of three enzymes carried with HIV (protease and integrase being the other two) and begins the process of integration of genetic material with the host genome. Reverse transcriptase first takes one of the RNA strands from HIV and, through reverse transcription, makes a RNA/DNA double helix. This hybrid helix returns to the transcriptase where the RNA is stripped and replaced with DNA making a viral DNA double helix
Integration – Integrase cuts off a 5’ and 3’ end of the new viral DNA (sticky ends) and moves it into the nucleus where it becomes integrated with the host genome.
Transcription – When the host cell is activated it reads the integrated viral DNA and uses the cells enzymes to create new viral enzymes which can be longer and more complex
Assembly – Protease cuts the longer HIV proteins (made by the host cell) into individual proteins. These will come together with the new viral genetic material and capsid proteins (also from protease) will be assembled into a new, but immature, virus
Budding – The new virus pushes itself out of the host cell taking with it part of the membrane and glycoproteins for infection of other cells.
The Pol domain encodes the viral PR, RT and IN proteins. Cleavage at this points by HIV protease will result in new infectious viral particles that are assembled by the Gag (Pr55) polyprotein.
This enzyme is responsible for the creation of new infectious particle and is sometimes referred to ask the bulldog enzyme.
Primary Function – When protease cleaves these polypeptides at specific points they become functional proteins. If cleavage doesn’t happen then the proteins will not function, thus the new viruses won’t mature to become infectious.ig
Figure – this figure shows the difference between an infectious and non-infectious HIV virus. Visualized by transmission electron microscopy and cryoelectron tomography. In the image on the right (infectious) there is a large red spot in the middle. That is the capsid that is made to hold the viral RNA particles as well as the infectious viral enzymes.
Active Site
The active site of HIV PR has two conserved aspartic acid residues on either side of the dimer. The catalytic residues Asp25 and Asp25’ (Asp125) are embedded in the convex hydrophobic core.
Semi-open Conformation
the opening of the two flexible flaps allows entry of the substrate peptide (or inhibitor), and upon closing these flaps coordinate the carboxamide groups flanking the scissle bond through a water molecule
Two proposed models of activation
The first model suggests a collision complex with HIV-1 protease in the open flap conformation as it enters the active site and induces the flaps to close.
The second model suggests the ligand approaches the HIV-1 protease in the semi-open flap and induces the flaps to adopt an open conformation to let the ligand bind.
Cleavage and activation are believed to be autocatalytic, but the details of this process are still not known.
Hydrolysis of Peptide bonds (Proteolysis)- the active site of these enzymes contain two highly conserved aspartic acid residues, one contributed from each lobe of the enzyme (Asp25 and Asp125). Each subunit is held together by hydrogen bonds with water as well as a pair of twofold related, antiparallel beta-hairpin structures. This is important when it comes to inhibitor design because the interactions with the enzyme and inhibitor will determine the enzyme conformation and whether it remains active or becomes inactive. Proteolysis is a very specific process where the enzyme will only cut where it wants to unlike acid hydrolysis where the polypeptide is cut everywhere.
These Phe-Pro, Tyr-Pro linkages are unique cleavage sites not subject to mammalian endopeptidase activity
Cleavage site sequences recognized by HIV PR on the Gag and Gag-Pol polyproteins. As you may or may not remember your amino acids there is a preference for cleavage points of amino acids that are hydrophobic and any aromatic compound is followed by a proline. These cleavage sites were determined by the N and C terminus points of mature viral particles. Efforts to predict where it would cleave is not known and may never be known since the diversity of retroviral proteases vary.
There is a common theme (general pattern) where most substrate sites where cleavage occurs has a branched amino acid at P2, a hydrophobic residue at P1, and an aromatic or proline at P1’. The exact reason why this happens is not fully known or documented.
Protease Inhibitors – this is an important step when it comes to treatment because this is where the proteins for making a mature and infectious virus happen. If this is blocked, then the subsequent virus will not mature and not be infectious
Structure-based Drug Design – This method of drug design generates target specific and potent inhibitors, but the downside is drugs developed by this method can only target one site at a time. Side-effects are also common with drugs made by this method such as: cellular toxicity, limited target choices, efficacy and applicability.
** no longer used as monotherapy and is strictly used to boost other PI and block cytochrome P450 activity
Clinical Efficacy
Atazanavir
Structure-based vs substrate based – SUBSTRATE: The idea was that peptide substrate analogues would be replaced with noncleaveable, transition-state isotere. This follows the mechanism of action by both HIV and cellular proteases under the acid-base chemistry to mimic the hydrated amide that represented the intermediate in amide hydrolysis catalyzed by the two active site aspartic acids. STRUCTURE: crystallography allowed for the realization that HIV PR is a homodimer with twofold symmetry that showed a new generation of inhibitors were needed that didn’t rely on structure or peptide mimicry.
First five generations
The isosteres of the amide hydrolysis transition states were studied. Pepstatin is a natural transition state mimic
Figure
These are the 6 structures of peptidomimetic subunits used for HIV protease inhibitors. Each spot outlined in grey represents the cleavage site for PR (non-cleavable in this case). These are structures that did not break through the process of proteolytic hydrolysis.
Hydroxyethylamine is the structure that was used for Saquinivir…the first approved PR inhibitor. This greatly increase water solubility and facilitated oral absorption
There were over 100 different compounds synthesized following methods similar to this one. The multitude of combination attempts made subnanomolar enzyme activity almost impossible to discover. Additions such as extension of the C-terminal end with a P’2 Ile-NHiBu group lost activity. The preference for (R)-stereochemistry of the hydroxyl group in 6 was much more dramatic. That is why compound 10 was greater than that of 11.
#8) beta-naphthoyl derivative
#9) quinolone-2-carboxamide
Stereochemistry played a huge part in this as well such as with compound 10 was 200-fold more effective than compound 11.
The first scheme didn’t work out all that well. It made bioavailability low and potency ineffective
The second scheme was the scheme used to produce the lead compound for saquinavir:
1) Esterification with (SOCl2, MeOH) and carbamate protection (ClCO2Me, H2O) of L-Phe
The inhibitor linkage is a hydroxyethylene group
Resistance –the virus evolves to accumulate a multitude of mutations within the protease that prevent Pis from binding to the protease. More than half the residues within the protease mutate in different combinations and lead to drug resistance. The protease is still able to recognize and process the natural substrate sites in the gag and Gag-pol polyproteins, while no longer being effectively inhibited by competitive drug molecules
Creation – If protease is blocked and no other HIV replication machinery is blocked the integrase will successfully implant viral DNA. This will code for the host cell to create new protease enzymes with a structure different (possibly) from the original.
Expensive – The average cost to a patient for these drugs (protease inhibitors) is around $20,000 annually
Time – The P.I. must be taken 3 times a day at precise times.
Drug-Drug Interactions – There are numerous accounts of bad drug-drug interactions when using protease inhibitors as both a monotherapy and combination therapy. Some PI and NNRTI counteract each other. PI and other medications for immunocompromised patients don’t work. Patients on cholesterol medication (Lipitor) must be given the lowest dose possible.
Side effects – fever, diarrhea, nausea, vomiting, abdominal pain, rash, fatigue and headaches. Although these symptoms vary between drugs they are common.
Patient Compliance – As with any drug treatment regimen it is important to take the precise dosage at the precise time for the duration of the treatment. When it comes to HIV/AIDS patients must have >95% compliance in order for the infection to be contained.
Genetic Polymorphisms – PI are metabolized by the CYP 3A4 isoenzyme family, but some PIs have been shown to inhibit this enzyme as well. Patients who have a polymorphism of the CYP 3A4 gene are sucepible to side effects such as inhibition of bilirubin conjugation leading to hyperbilirubinemia. Polymorphisms of apolipoproteins, cholesteryl ester transfer proteins
Allosteric Inhibitors – attempt to bind and induce a permanent conformational change.
BVM specifically inhibits CA-SP1 cleavage late in the Gag cleavage cascade. Biochemical studies have demonstrated an accumulation of uncleaved CA-SP1 intermediates in cells treated with BVM. Structure of the BVM binding site is not known. It is accepted that the CA-SP1 region of Gag adopts an alpha-helical conformation via computer modelling prediction software.