This presentation covers all approved therapy for the treatment of AIDS with their mechanism. It also includes some examples of new coming technology for treatment.

1. Small molecule
therapy for AIDS
Presented by-
Sushant Balasaheb Jadhav
Roll No. – 18PBT206
M. Tech. Pharmaceutical Biotechnology
Institute of Chemical Technology, Mumbai
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CONTENTS
 HIV Structure
 The HIV Life Cycle
 Drug Discovery Approaches
 Drug Classification
 Limitations Of Currently Available Agents
 Causes Of Treatment Failure
 Highly Active Antiretroviral Therapy (HAART)
 Prophylaxis
 The Future Scope/Pipeline
 HIV Capsid
 Bispecific Antibody (BiAb)

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HIV STRUCTURE

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THE HIV
LIFE CYCLE

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HIV-1 HIV-2
This strain is found
worldwide and is more
common.
This strain is found
predominantly in West Africa.
This strain is more likely to
progress and worsen.
This strain is less likely to
progress and many of those
infected remain lifelong non-
progressors. Progression is
slower.
Average level of immune
system activation are
higher.
Average level of immune
system activation are lower.
During progression, HIV-1
has lower CD4 counts than
HIV-2.
During progression, CD4
counts are higher in this strain.
Plasma viral loads are
higher.
Plasma viral loads are lower.

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Classification of HIV-1
 M (the major group), N, O (the outlier group), and P
 CRFs (circulating recombinant forms)

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Drug Discovery Approaches
 High throughput compound screens with virus-
specific replication or enzymatic assays
 Optimization of inhibitors using lead compounds
based on homologous enzymes or targets
 Rational drug design modeled on the structures of
viral proteins

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DRUG CLASSIFICATION
 Reverse Transcriptase Inhibitors
1. Nucleoside (NRTIs)
2. Non-Nucleoside (NNRTIs)
 Protease Inhibitors (PI)
 CCR5 Antagonists (Entry Inhibitors)
 Fusion Inhibitors
 Integrase Strand Transfer Inhibitors (INSTIs)

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DRUG CLASSIFICATION

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FDA
Approval of
HIV
Medicines

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Nucleoside Reverse Transcriptase
Inhibitors (NRTI)
 First class of antiretrovirals
 Must undergo intracellular
triphosphorylation to become
active against HIV
 Adverse effects: nausea,
headache, lactic acidosis,
anemia (AZT), peripheral
neuropathy, pancreatitis,
lipodystrophy

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Nucleoside Reverse Transcriptase
Inhibitors (NRTI)

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 Mechanism of
action
Nucleoside Reverse Transcriptase
Inhibitors (NRTI)

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Nucleoside Reverse Transcriptase
Inhibitors (NRTI)
Resistance to NRTIs is mediated by two mechanisms:
1. ATP-dependent pyrophosphorolysis, which is the
removal of NRTIs from the 3’ end of the nascent
chain, and reversal of chain termination.
2. Increased discrimination between the native
deoxyribonucleotide substrate and the inhibitor.

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 NNRTI’s inhibit the HIV reverse
transcriptase by binding to hydrophobic
pocket close to the active site
 Lock the enzyme’s active site in an inactive
conformation
 Potent but subject to rapid emergence of
resistance
 Active against HIV-1 (exception group O) but
NOT active against HIV-2
Non-Nucleoside Reverse Transcriptase
Inhibitors (NNRTI)

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Non-Nucleoside Reverse Transcriptase
Inhibitors (NNRTI)

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Non-Nucleoside Reverse Transcriptase
Inhibitors (NNRTI)

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Protease Inhibitors (PI)
 Third class of antiretroviral agents developed
 Revolutionized therapy following introduction in
1995
 Inhibit HIV protease by binding to its active site,
preventing the cleavage of gag and gag-pol precursor
proteins
 Virions are produced but they are incomplete and
non-infectious
 Side effects: abdominal upset, diarrhea, dyslipidemia,
lipodystrophy, atherosclerosis

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Protease Inhibitors (PI)

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Steps followed by HIV-1 to become PI resistant
1. Acquisition of primary resistance mutations in the
protease gene
2. Selection of secondary protease mutations to repair
the enzymatic function and rescue viral fitness
3. Selection of mutations in the major cleavage sites of
the gag and gag-pol polyprotein precursors that
restore protein processing and increase production of
the HIV-1 protease itself
Protease Inhibitors (PI)

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CCR5 Antagonists (Entry Inhibitors)

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CCR5 Antagonists (Entry Inhibitors)

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Fusion Inhibitors
 Single drug approved,
Enfuviritide.
 FDA approval 2003.
 Expensive and only
subcutaneous dosing
options available.
 Used as salvage therapy in
combination with other
treatments for multidrug
resistant strains of HIV.

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Entry Inhibitors & Fusion Inhibitors

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Integrase Strand Transfer Inhibitors

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 It binds to two Mg+ ions in integrase and viral DNA
preventing their contact
 Inhibits DNA strand transfer into host-cell genome
and thus prevents viral integration
 Very potent in-vitro and in-vivo
 Does not confer resistance to other ART classes
 Works synergistically with all ART’s studied
 Has few side effects and drug interactions
Integrase Strand Transfer Inhibitors

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Integrase Strand Transfer Inhibitors

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Limitations of Currently Available Agents
Toxicities and adverse effects
Emergence of resistance
Negative effects on quality of life, “treatment fatigue”
Drug-class cross resistance
Drug interactions (esp NNRTIs, PIs and CCR5
blocker)
Complexity of “salvage regimens”
Cost, especially in “resource limited” settings

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Causes of Treatment Failure
 Emergence of baseline drug resistance
 Incomplete adherence
 Variable pharmacologic metabolism
 Insufficiently potent regimens
 Viral sanctuaries
 Host immune status

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Highly Active Antiretroviral Therapy
(HAART)
 Lifecycle of virus is as short as ~1.5 days
 Virus lacks proofreading enzymes
 High mutation rate leads to high resistance rate
 First fixed-dose combination approved in 1997. 14
FDA approvals to date
 Combinations contain up to 4 API molecules.
 1997-2004 GSK leader in approvals. 2004-Present
Gilead leader in approvals.
 Until 2006 all FDCs contained single drug class (ex:
only NRTIs)

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Time frame for antiretroviral drug action during a
single-cycle HIV-1 replication assay

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Highly Active Antiretroviral Therapy
(HAART)

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PROPHYLAXIS
 Post-exposure prophylaxis [PEP]
1. Occupational
2. Non-occupational
 Pre-Exposure Prophylaxis [PrEP]

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Pharmacokinetic Enhancers
 Approved 2014. Developed
by Gilead.
 Inhibits liver enzyme
CY3PA, which is responsible
for the metabolism of
several HIV treatments.
 Taken in combination with
HAART to minimize loss of
drug efficacy.

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The Future Scope/Pipeline
 4 or 8 week dosing trials for cabotegravir/rilpivirine
in Phase II trials.
 BMS has 2 single drug treatments in clinical trials
with new mechanisms of action.
1. Attachment inhibitors
2. Maturation inhibitors
 Monoclonal Antibodies entering Phase II trials for
HIV treatment.

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The Future Scope/Pipeline

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HIV Capsid
 New class of small molecule antiretroviral
compounds
1. PF-1385801
2. PF-3759857
3. PF-3450071
4. PF-3450074
 The compounds exhibit potent antiviral activity
against HIV-1 laboratory strains, clinical isolates,
and HIV-2
 Inhibit both early and late events in the viral
replication cycle.

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HIV Capsid

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HIV Capsid

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Bispecific Antibody (BiAb)
 Binds both an HIV-1 specific T-cell receptor and an
effector T cell
 A next generation of bispecific reagent has linked
epitope-specific TCRs to an single-chain variable
fragment (scFv) specific for a cytotoxic cell to effect
what has been termed “immune-mobilizing
monoclonal TCRs,” called “ImmTAVs” for targeting
virus antigens.
 The first in vitro use of an anti-HIV-1 ImmTAV is
described in the report by Yang et al. as a TCR
specific for HIV-1 p17 cloned and genetically linked to
an scFv that binds to CD3+CD8+ T cells (CD8).

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REFERENCES
Small Molecule HIV Treatments - G. McKenna, WHO
2016
https://aidsinfo.nih.gov/guidelines/htmltables/1/6403
HIV-1 Antiretroviral Drug Therapy - Eric J. Arts and
Daria J. Hazuda
Antiretroviral Drugs in the Treatment and
Prevention of HIV Infection - Noga Shalev, MD
HIV Capsid is a Tractable Target for Small Molecule
Therapeutic Intervention - Wade S. Blair et. al.
 A New Agent in the Strategy to Cure AIDS - John A
Zaia

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