MSOP1016: Science of Medicines 3 - Antiviral Drugs Against RNA Viruses

HIV and AIDS

• HIV (Human Immunodeficiency Virus) is a type of retrovirus that causes AIDS (Acquired Immune Deficiency Syndrome)
• AIDS is a condition where the immune system is severely weakened, making the body susceptible to opportunistic infections and cancers
• HIV infects T-cells of the immune system, which are vital for fighting infections

Life Cycle of HIV

• HIV life cycle involves seven stages: binding, fusion, reverse transcription, integration, replication, assembly, and budding
• HIV uses its reverse transcriptase enzyme to convert its RNA genome into DNA, which is then integrated into the host cell's genome
• The integrated DNA is transcribed into mRNA, which is translated into HIV proteins
• The proteins are assembled into new viral particles, which bud from the host cell

Anti-HIV Therapies

• Antiretroviral therapy (ART) is a combination of drugs that target different stages of the HIV life cycle
• Types of HIV therapies:
  • Nucleoside reverse transcriptase inhibitors (NRTIs)
  • Non-nucleoside reverse transcriptase inhibitors (NNRTIs)
  • Protease inhibitors (PIs)
  • Fusion inhibitors
  • Integrase inhibitors

Nucleoside Reverse Transcriptase Inhibitors (NRTIs)

• NRTIs are nucleoside analogs that inhibit the action of HIV reverse transcriptase
• Examples of NRTIs:
  • Zidovudine (AZT)
  • Didanosine (DdI)
  • Lamivudine (3TC)
  • Emtricitabine (FTC)
  • Abacavir (ABC)
• NRTIs need to be triphosphorylated to be active
• They inhibit reverse transcriptase and act as chain terminators

Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)

• NNRTIs bind to an allosteric site of reverse transcriptase, causing a conformational change that inhibits the enzyme
• Examples of NNRTIs:
  • Nevirapine
  • Delavirdine
  • Efavirenz
  • Rilpivirine
• NNRTIs are non-competitive, reversible inhibitors

Protease Inhibitors (PIs)

• PIs inhibit the action of HIV protease, which is essential for the production of mature viral particles
• Examples of PIs:
  • Saquinavir
  • Ritonavir
  • Indinavir
  • Nelfinavir
  • Amprenavir
• PIs are designed to have low peptidic character to improve oral bioavailability

HAART (Highly Active Antiretroviral Therapy)

• HAART is a combination of three or more antiretroviral drugs, including NRTIs, NNRTIs, and PIs
• HAART reduces the viral load, increases CD4+ cell count, and improves survival
• HAART is a lifelong treatment, and adherence to the regimen is crucial to prevent resistance and treatment failure### Stereochemistry and HIV-Protease Inhibitors
• The P1' position is crucial in HIV-protease inhibitors due to stereochemistry considerations.
• Initial inhibitors were based on peptides, but they had high molecular weight, poor oral bioavailability, and were prone to mutation.

Design of HIV-Protease Inhibitors

• The design focused on the S1-S1' region, then extended to interact with S2/S3 and S2'/S3' sites.
• Desirable features of protease inhibitors (PIs) include:
  • Low molecular weight
  • Good oral bioavailability
  • Good water solubility
  • Selective for viral protease
  • Activity unaltered by mutation of viral protease

First-Generation Protease Inhibitors

• Saquinavir (1995) was the first protease inhibitor used clinically.
• It was designed from a peptide lead compound, but had high molecular weight, poor oral bioavailability, and was prone to drug resistance.

Saquinavir Development

• The lead compound was developed from a pentapeptide sequence containing the susceptible Phe-Pro linkage.
• The design involved introducing a transition-state isostere, adding Asn to make it more peptidic, optimizing the N-terminus, and optimizing the C-terminus.
• This resulted in a 40-fold, 8-fold, and 60-fold increase in activity, respectively.

Saquinavir Binding Interactions

• Five subsites (S3-S2') are occupied, with the transition state isostere interacting with the catalytic aspartates.
• Carbonyls act as hydrogen bond acceptors to the bridging water molecule in the flap region.

Tipranavir

• It was designed from a non-peptide lead compound, using high-throughput screening of 5000 compounds.
• The design involved multiple synthetic and optimization steps, resulting in a compound with increased metabolic stability.
• Tipranavir has a Ki of 8 pM and an IC50 of 30 nM.

Other Protease Inhibitors

• Ritonavir (1996) and Indinavir (1996) were designed using a hybridization strategy.
• Nelfinavir (1997) and Amprenavir (1999) were designed using a non-peptide-like approach, using saquinavir as a lead compound.
• Darunavir and Atazanavir (2003) were designed using a combination of approaches.
• Lopinavir and Tipranavir are the most recent protease inhibitors to market.

Protease Inhibitors Summary

• Protease inhibitors can be designed from non-peptidic or peptidic lead compounds.
• Key features include:
  • Transition state isostere
  • Maximizing interaction with subsites in the receptor
  • Keeping the molecular weight small
  • Improving solubility
  • Using bioisosteres
  • Avoiding mutation issues
  • Improving metabolic stability

HIV Life Cycle

• The HIV protease enzyme is involved in the viral life cycle, cleaving peptide bonds and releasing the virion.
• The enzyme has broad substrate specificity, but can be inhibited by protease inhibitors.

HIV Protease Enzyme

• The enzyme is a symmetrical dimer, composed of two identical protein units.
• The active site is located at the interface between the two protein units, with two fold rotational symmetry.
• The enzyme has broad substrate specificity, but can be inhibited by protease inhibitors.

HIV Protease Inhibitors in HAART Treatment

• HIV protease inhibitors are used in combination with other antiretroviral drugs in HAART (Highly Active Antiretroviral Therapy) treatment.
• The treatment has been successful in reducing the viral load and improving the quality of life for HIV patients.