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

What type of virus is HIV considered to be?

  • Adenovirus
  • DNA virus
  • RNA virus
  • Retrovirus (correct)

    • Which type of HIV is mainly found in Western Africa?

  • HIV subtypes
  • HIV M group
  • HIV 1
  • HIV 2 (correct)

    • What is the primary enzyme targeted by Nucleoside Reverse Transcriptase Inhibitors (NRTIs)?

  • RNA polymerase
  • DNA polymerase
  • Protease enzyme
  • Reverse transcriptase (correct)

    • Which antiviral agent specifically inhibits the HIV protease enzyme?

    <p>Tipranavir</p> Signup and view all the answers

    Why are some HIV-1 M group subtypes considered to be more virulent?

    <p>Higher resistance to medications</p> Signup and view all the answers

    What characteristic of RNA viruses makes them prone to rapid mutation?

    <p>Error-prone replication process</p> Signup and view all the answers

    Which of the following sources provides information on approved antiviral drugs over the past 50 years?

    <p>Clinical Microbiology Reviews by De Clercq E and Li G</p> Signup and view all the answers

    Which edition of 'An Introduction to Medicinal Chemistry' by Graham Patrick is referenced in the text?

    <p>5th Edition, 2013</p> Signup and view all the answers

    Which chapter of 'Foye’s Principles of Medicinal Chemistry' discusses the conventional nucleoside analogues?

    <p>Chapter 40</p> Signup and view all the answers

    Which of the following is not a class of therapeutic agents used in the treatment of HIV?

    <p>Antiretroviral agents</p> Signup and view all the answers

    Which of the following sources provides information on the strategies employed for the development of newer generations of antiviral drugs?

    <p>Lecture 14 - Nucleoside &amp; Nucleotide analogues</p> Signup and view all the answers

    Which of the following sources provides information on the acyclic nucleoside analogues?

    <p>Foye’s Principles of Medicinal Chemistry</p> Signup and view all the answers

    Why is it recommended to take 2-3 drugs of different classes to minimize the risk of resistance?

    <p>To lower the mutation chance of HIV</p> Signup and view all the answers

    What is the probability of developing resistance when taking three different drugs with a mutation chance of 1:10,000 each?

    <p>1 in 1 trillion</p> Signup and view all the answers

    Which component of HIV treatment aims to avoid resistance despite ongoing mutation risks?

    <p>Protease Inhibitors (PIs)</p> Signup and view all the answers

    What is the primary reason for patients needing to take HAART for the rest of their lives?

    <p>To avoid an increased risk of developing resistance</p> Signup and view all the answers

    What is the main advantage of combining multiple drugs into a single HAART pill?

    <p>To simplify the administration schedule for patients</p> Signup and view all the answers

    Which class of drugs is referred to as nucleoside analogues and requires triphosphate activation to be effective?

    <p>Nucleoside Reverse Transcriptase Inhibitors (NRTIs)</p> Signup and view all the answers

    Which type of drug is Zidovudine (AZT)?

    <p>Nucleoside reverse transcriptase inhibitor</p> Signup and view all the answers

    What is the unique characteristic of the enzyme reverse transcriptase that makes it an ideal target for HIV drugs?

    <p>It is a type of DNA polymerase unique to HIV</p> Signup and view all the answers

    Which drug was the second HIV drug approved in the USA in 1988?

    <p>Didanosine (DdI)</p> Signup and view all the answers

    How do nucleoside reverse transcriptase inhibitors (NRTIs) need to be activated to be effective against HIV?

    <p>They must be converted to triphosphate by cellular enzymes</p> Signup and view all the answers

    What is the role of Zalcitabine in HIV treatment?

    <p>Nucleoside reverse transcriptase inhibitor</p> Signup and view all the answers

    Which process do Integrase inhibitors target in the HIV life cycle?

    <p>Replication of genome</p> Signup and view all the answers

    Why do nucleoside reverse transcriptase inhibitors (NRTIs) need to ensure selectivity despite targeting reverse transcriptase?

    <p>To maintain safety and avoid adverse effects</p> Signup and view all the answers

    Which drug is an adenosine analogue used against HIV and/or Hepatitis B?

    <p>Tenofovir</p> Signup and view all the answers

    What is the main difference between Adefovir and Tenofovir?

    <p>Adefovir has a sulfur group, unlike Tenofovir</p> Signup and view all the answers

    What is the role of gp41 in the adsorption and penetration process of HIV?

    <p>It undergoes a conformational change to allow virus and cell to be pulled together</p> Signup and view all the answers

    What is the function of the viral protein integrase in the life cycle of HIV?

    <p>It catalyzes the addition of viral RNA into the host cell DNA</p> Signup and view all the answers

    What is the significance of the (+)vRNA/(-)vDNA hybrid in the replication of HIV genome?

    <p>It is the intermediate step in the formation of dsDNA from vRNA</p> Signup and view all the answers

    Which viral enzymes have been identified as possible targets for developing therapeutics against HIV?

    <p>Reverse transcriptase, protease, and integrase</p> Signup and view all the answers

    What is the role of the viral protein Vpu in the budding process of HIV?

    <p>It binds to CD4 on host membrane and tags it with ubiquitin</p> Signup and view all the answers

    What is the purpose of pre-exposure prophylaxis (PrEP) in the prevention of HIV transmission?

    <p>To be used as a medication for people with increased risk of infection</p> Signup and view all the answers

    What is the time frame for post-exposure prophylaxis (PEP) to be effective in preventing HIV transmission after exposure?

    <p>Best within 1 hour and still effective up to 3 days</p> Signup and view all the answers

    Which viral proteins are involved in the capsid structure of HIV?

    <p>p24, matrix protein (p17), and gp120</p> Signup and view all the answers

    What is the role of CD4 proteins on host T-cells in the adsorption and penetration process of HIV?

    <p>They interact with gp120 and undergo a conformational change</p> Signup and view all the answers

    How does the viral enzyme reverse transcriptase contribute to the replication of the HIV genome?

    <p>It converts (+)vRNA/(-)vDNA hybrid into dsDNA</p> Signup and view all the answers

    What were the desirable features of Protease Inhibitors (PIs) according to the text?

    <p>Good water solubility and selectivity for viral protease</p> Signup and view all the answers

    Which compound was the most recent protease inhibitor to enter the market according to the text?

    <p>Tipranavir</p> Signup and view all the answers

    What disadvantage is associated with Saquinavir as mentioned in the text?

    <p>High molecular weight</p> Signup and view all the answers

    What was the strategy employed in the design of Ritonavir (1st generation) and Lopinavir (2nd generation) protease inhibitors?

    <p>Symmetry of active site</p> Signup and view all the answers

    What was the aim of simplification in the drug design process for Saquinavir?

    <p>To improve solubility and reduce peptide character</p> Signup and view all the answers

    Which compound was designed using a hybridization strategy with saquinavir as half of the lead?

    <p>Indinavir</p> Signup and view all the answers

    What factor was considered in subsequent research on modern protease inhibitors to reduce from precursor analogues?

    <p>Reduce peptide character</p> Signup and view all the answers

    What is the primary mechanism of action of non-nucleoside reverse transcriptase inhibitors (NNRTIs)?

    <p>Non-competitive inhibition of the allosteric site of reverse transcriptase</p> Signup and view all the answers

    Which of the following is a common issue with first-generation NNRTIs?

    <p>Rapid mutation of the binding site</p> Signup and view all the answers

    Which of the following is a characteristic of second-generation NNRTIs?

    <p>They are active against both resistant variants and wild-type viruses</p> Signup and view all the answers

    Which of the following is a difference between NNRTIs and protease inhibitors (PIs)?

    <p>PIs are not prodrugs and can be used in in vivo assays to test activity</p> Signup and view all the answers

    Which of the following is a characteristic of the precursor polyproteins for HIV?

    <p>They are cleaved by viral protease into smaller viral proteins</p> Signup and view all the answers

    Which of the following is a common issue with peptide-based HIV drugs?

    <p>Susceptibility to metabolism and rapid excretion</p> Signup and view all the answers

    Which of the following is a difference between first-generation and second-generation NNRTIs?

    <p>Second-generation NNRTIs are less susceptible to resistance due to their ability to form hydrogen bonds with the main peptide chain</p> Signup and view all the answers

    Which of the following is a characteristic of Efavirenz, Etravirine, and Rilpivirine?

    <p>They are not second-generation NNRTIs</p> Signup and view all the answers

    Which of the following is a difference between NNRTIs and nucleoside reverse transcriptase inhibitors (NRTIs)?

    <p>NRTIs and NNRTIs can be used together to avoid resistance</p> Signup and view all the answers

    Which of the following is a characteristic of protease inhibitors (PIs)?

    <p>They are not active against both resistant variants and wild-type viruses</p> Signup and view all the answers

    What is the function of the viral protein Vpu in the HIV life cycle?

    <p>It binds to the host membrane and tags CD4 proteins with ubiquitin for removal.</p> Signup and view all the answers

    What is a unique characteristic of the HIV protease enzyme that differs from mammalian proteases?

    <p>It has broad substrate specificity and can cleave peptide bonds next to proline.</p> Signup and view all the answers

    Which amino acid residues in the HIV protease enzyme monomers are crucial to the reaction mechanism?

    <p>Asp-25 and Asp-25' from each monomer.</p> Signup and view all the answers

    What is the primary function of HIV protease inhibitors?

    <p>To block the cleavage of viral polyproteins into functional proteins.</p> Signup and view all the answers

    Which type of tetrahedral intermediate is involved in the reaction mechanism of the HIV protease enzyme?

    <p>Bridging water-dependent tetrahedral intermediate.</p> Signup and view all the answers

    Which of the following is a common feature of HIV protease inhibitors and renin inhibitors?

    <p>They both mimic the transition state of the reaction mechanism.</p> Signup and view all the answers

    What is the primary purpose of introducing a stable tetrahedral feature in the design of HIV protease inhibitors?

    <p>To increase the binding affinity to the enzyme.</p> Signup and view all the answers

    What is the role of the hydroxyethylamine isostere in the design of HIV protease inhibitors?

    <p>It mimics one of the TS hydroxyls and stabilizes the tetrahedral intermediate.</p> Signup and view all the answers

    Which of the following best describes the substrate binding and cleavage process in the HIV protease enzyme?

    <p>The substrate binds to the enzyme, and the flaps close over the active site, followed by cleavage.</p> Signup and view all the answers

    Which of the following statements best describes the similarities between the two variants of HIV protease (HIV-1 and HIV-2)?

    <p>They have a 50% sequence match and share most binding subsites.</p> Signup and view all the answers

    Study Notes

    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.

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    Description

    Explore the topic of antiviral drugs specific to RNA viruses, focusing on HIV. Learn about approved antiviral drugs over the past 50 years and their mechanisms of action. This quiz is based on the lecture L14 and recommended reading from the Medway School of Pharmacy.

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