This document provides an overview of HIV, its mechanisms, and various classes of antiretroviral drugs including CCR5 inhibitors, NNRTIs, and integrase inhibitors. It discusses the history of HIV, modes of transmission, the drug lifecycle, and the structure and mechanism of action of these therapeutic agents. Key examples and chemical synthesis processes for each drug class are highlighted, illustrating their roles in inhibiting HIV replication.

1. Pharmaceutical
chemistry
Understanding the Mechanisms and
therapeutic advances of CCR5 Inhibitors,
NNRTIs, and Integrase Inhibitors
By group 9

2. Members
• KABUUKA RICHARD
• NOURELDEIN ABDALLA
MOHAMED
• KAGOYA AGNESS
• KOBUSINGYE PHIONA

3. content outline
 HIV Overview ;Introduction, History, and Mechanisms
 Drug Classifications and Mechanisms of Action
CCR5 Receptor Inhibitors
 Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)
 Integrase Inhibitors
 References

4. HIV
Human Immunodeficiency Virus (HIV) causes immune
suppression by targeting CD4+ T cells.
First identified in 1981 during unusual cases of pneumonia in
the U.S.

5. History
• 1983: Identification of HIV-1 by Luc Montagnier and
Robert Gallo.
• 1985: First HIV antibody test approved.
• 1996: Introduction of Highly Active Antiretroviral
Therapy (HAART).
• 2007: First CCR5 inhibitor (Maraviroc) approved.

6. How HIV is acquired
Modes of Transmission:
 1. Sexual contact (unprotected vaginal/anal sex).
 2. Blood exposure (contaminated needles, transfusions).
 3. Vertical transmission (mother to child during childbirth or breastfeeding).
Risk factors
 High-risk sexual behaviors.
 Presence of other sexually transmitted infections (STIs).
 Unsafe healthcare practices in resource-limited settings.

7. Immune Cells Attacked
 CD4+ T cells.
 Macrophages
 dendritic cells
 monocytes.
This leads to;
• Loss of CD4+ cells leading to impaired immune response.
Increased susceptibility to opportunistic infections.

8. Receptors
• CD4 receptor: Primary binding site for the HIV gp120 protein.
• Co-receptors: CCR5 and CXCR4.

9. Mechanism of entry
1. HIV gp120 binds to CD4.
2. gp120 binds to CCR5 or CXCR4.
3. gp41 facilitates viral entry into the host cell.

10. HIV Life Cycle

12. Classification of HIV drugs
1. Entry Inhibitors: Block virus-cell attachment ; CCR5 inhibitors.
2. Reverse Transcriptase Inhibitors: Prevent reverse transcription.
• Nucleoside RTIs (NRTIs).
• Non-Nucleoside RTIs (NNRTIs).
3. Integrase Inhibitors: Block integration into host DNA.
4. Protease Inhibitors: Prevent viral maturation.

14. CCR5 Receptor Inhibitors
• These drugs block the CCR5 co Receptor preventing HIV entry
• Examples include; Maraviroc and Vicriviroc
• They are only effective in CCR5 tropic HIV-1
• Maraviroc was the first approved CCR5 Inhibitor by FDA in
2007.
• The CCR5 receptor was discovered by Nathan Landau and
Joseph in 1996.

15. CCR5 receptor

16. Mechanism of Action
• Bind to transmembrane region of CCR5 ;preventing gp120-
CCR5 interaction.
• Without receptor binding,the virus cannot complete
membrane fusion thus blocking entry into the cells.
• By blocking viral entry at the initial step,CCR5 Inhibitors
prevent the virus from infecting new cells

18. Chemical structure
• Piperazine core;for binding the hydrophobic CCR5 pocket.
• Benzyl group with methyl sulfonyl subsituition;enhances
receptor selectivity.
• Cyclohexane carboxamide group; improves binding affinity and
lipophilicity.

19. Maraviroc

20. synthesis

21. Integrase Inhibitors
• First approved drug was Raltegravir (FDA, 2007).
• Discovery: Integrase enzyme identified as a key target for blocking HIV
replication in the 1990s.
• Pioneering researchers: Dr. Edward A. Berger and collaborators.
• MOA;Blocking integrase prevents integration of viral DNA into the host
genome, halting replication.

22. Integrase Inhibitors;structure
• 1. Raltegravir: 2-benzylpyrimidinone scaffold.
• 2. Dolutegravir: Improved resistance profile and
pharmacokinetics.
• 3. Bictegravir: High potency and fewer side effects.
Metal-binding pharmacophore (binds Mg2+ in the integrase
active site).

23. Integrase Inhibitors; Chemical Synthesis
steps
1. Functionalization of core pyrimidine or quinolone scaffold.
2. Introduction of pharmacophores for integrase binding.
3. Optimization for potency and bioavailability.
Dolutegravir synthesis involves multi-step reactions starting with quinoline
derivatives.

24. Integrase Inhibitors: Mechanism of Action
• Integrase inhibitors bind to the active site of the HIV integrase
enzyme.
• Chelate essential metal ions (Mg2+) needed for DNA strand
transfer.
• Prevent integration of viral DNA into the host genome, halting
replication.

26. Integrase Inhibitors,Structure-Activity Relationship
1. Metal-binding group: Essential for activity (e.g., β-diketo acids or
isosteres).
2. Lipophilic tail: Enhances binding to hydrophobic pockets in the
active site.
3. Modifications: Improve bioavailability and resistance profiles
(e.g., Dolutegravir modifications).

27. Raltegravir

28. Integrase inhibitors synthesis

29. NNRTIs: History
• First approved drug: Nevirapine (FDA, 1996).
• Developed to target HIV-1 specifically by binding to reverse transcriptase.
• Discovery era: Late 1980s, as alternative to NRTIs.
• Advantages: Non-competitive inhibition and lower cross-resistance with
NRTIs.

30. NNRTIs: Structure
• Examples:
1. Efavirenz: Tricyclic pyrimidine structure.
2. Nevirapine: Dipyridodiazepinone core.
3. Etravirine: Diarylpyrimidine derivative.
• Key feature: Non-nucleoside scaffold that binds allosterically to
reverse transcriptase.

31. NNRTIs: Chemical Synthesis
• Synthetic pathways:
1. Efavirenz: Multi-step synthesis involving cyclization of fluorobenzene
derivatives.
2. Nevirapine: Synthesis involves condensation reactions of diazepinone
cores.
• Goal: Optimize yield, stereoselectivity, and scalability for mass
production.

32. Synthesis

33. NNRTIs: Mechanism of Action
• NNRTIs bind non-competitively to the reverse transcriptase
enzyme.
• Induce conformational changes that inhibit DNA
polymerization.
• Target HIV-1 specifically, sparing host cellular enzymes.

34. MOA

35. NNRTIs: Structure-Activity Relationship
• Flexible linkers: Essential for accommodating allosteric binding pocket.
• Halogen substitutions: Improve lipophilicity and cell penetration.
• . Modifications: Enhance potency and reduce resistance (e.g., Etravirine
design).

36. SAR

37. References
• 1. Golan, D. E., et al. "HIV Pharmacology and Mechanisms of
Action."
• 2. Landovitz, R. J., et al. "Advances in Antiretroviral Therapy."
• 3. WHO Guidelines on HIV Treatment: https://www.who.int.

38. END
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