What are some problems involved with developing antiviral drugs compared to other drugs?
- Viruses use the synthetic machinery of the host cell. But, processes unique to the virus can be exploited (e.g. polymerases, proteases).
- Some viruses become latent for extended periods of time during which there is little biosynthetic activity to target.
- Acute infections may be short and clinical symptoms do not become apparent until virus replication is finished.
- Some viruses do not grow in tissue culture and there is no animal model.
- Mutations can arise at a rapid rate and generate resistant populations (“escape mutants”).
What are some strategies for developing antiviral drugs?
- Drugs can target virus functions which have no host cell counterpart.
- A drug may be more effective against a virus function than the cellular equivalent.
• A pro-drug may be specifically activated by a viral
enzyme.
- The drug may target both virus and host cell.
- High throughput screening of chemical libraries.
- Designer drugs: knowledge of viral protein structure, synthesis of targeted chemicals, computer-derived structure predictions.
What are 4 goals in antiviral drug development?
- Molecular mechanism of action needs to be determined
- Compound should block viral spread early to limit cytopathology and cytokine-inflammatory response
- Replication should be blocked completely to avoid development of persistence and/or resistance
- Resistance to drug must be manageable
What are the Drugs that Affect Viral Replication by Interfering with Viral DNA Polymerases or Reverse Transcriptase of HIV? How are they further grouped?
Acyclovir and gancicyclovir (Guanosine Analogues that don’t have a phosphate group…thymidine kinase), cidofovir and adefovir and tenofovir (Acyclic Nucleoside Phosphonates), ribavirin,
What is the mechanism of action of acyclovir and gancicyclovir? How is specificity for virus established? Is resistance a problem and how is it established?
- Acyclovir’s ribose lacks 3’OH needed for daughter strand chain elongation. Get chain termination.
- Ganciclovir’s ribose has an OH that functions poorly as a primer for chain elongation. Get addition of one more nucleotide, and then stalling of the viral DNA polymerase.
- Antiviral activity results from differences in activity of viral and cellular thymidine kinases
- Viral DNA polymerase has higher affinity for ACV-PPP and GCV-PPP than does host DNA polymerase
- Resistance not large problem, but occurs when mutations:
- -destroy or reduce activity of viral thymidine kinase
- -reduce the affinity of viral polymerase for ACV-PPP
What is acyclovir used to treat and how does it do so?
Acyclovir is Used to Treat Infections by HSV Types 1 and 2 and VZV (shingles)
- HSV and VZV thymidine kinase phosphorylates acyclovir to monophosphate
- Cellular enzymes make the di- and triphosphate
- HSV and VZV DNA polymerases have greater affinity for ACV-PPP than cellular DNA polymerase
- ACV-PPP is competitive inhibitor for dGTP; is incorporated into DNA daughter strand; acts as chain terminator; and “freezes” the viral DNA polymerase on the DNA and inactivates the polymerase
- Treat cold sores (HSV-1), genital herpes (HSV-2), shingles (zoster) (VZV)
- Treat immunodeficient patients (transplant, AIDS) in which latent HSV and VZV reactivate
What is gancicyclovir used to treat and how does it do it? Is it more or less toxic than acyclovir?
Ganciclovir is Used to Treat Cytomegalovirus (CMV) Infections in Immunodeficient Patients in Which CMV Reactivates
- CMV does not have a thymidine kinase
- CMV-coded phosphokinase converts ganciclovir to monophosphate form
- Cellular kinases make the tri-phosphate form
- CMV DNA polymerase has greater affinity for triphosphate substrate than does cellular DNA polymerase
- GCV-PPP acts as a competitive inhibitor for dGTP, is incorporated into DNA daughter strand, is not obligate chain terminator but causes stalling of viral DNA polymerase after it incorporates one more nucleotide
- Cell DNA polymerase can use GCV-PPP (poorly) so GCV-PPP is more toxic than ACV-PPP
What are some other forms of acyclovir and gancicyclovir and how do they work?
- Valganciclovir (GCV with valine group) is bioavailable form that is used commonly (given orally)
- Valacyclovir are now the gold standard for use against HSV infections because of bioavailability and longer half life in vivo
- Have approximately 5-fold increase in bioavailability over acyclovir
- Are prodrugs that are active in cells that cleave off side chain
• Are then activated by the HSV and VZV thymidine kinase
– Like acyclovir, are inactive against herpes viruses that do not encode thymidine kinase
–Have greater activity than Acyclovir against some herpes viruses (example: VZV)
What are the mechanisms of action of cidofovir and tenofovir?
They are nucleotide analogs with one phosphate group so they only require cellular kinases to be phosphorylated. They work b/c some viral DNA polymerases have a higher affinity for them.
Cidofovir works against DNA viruses. It results in either chain termination or mutagenic viral DNA.
How is cidofovir used? What is its bioavailability? What is its toxicity? How can those things be improved?
• Cidofovir—CMV retinitis in AIDS patients.
- -Stockpiled for use against smallpox or monkeypox.
- -Used “off label” against molluscum contagiosum (poxvirus skin infection), adenovirus, HPV, BK virus, JC virus.
- -Poorly bioavailable. Accumulates in kidney—nephrotoxic.
- -New lipid-linked derivatives of cidofovir and other acyclic nucleoside phosphonates are much more bioavailable and less toxic; in clinical trials.
How is tenofovir used? What is its bioavailability?
• Tenofovir disoproxil fumarate– HIV infections: used in in combination with a nucleoside analog; the drug is named Truvada.
Licensed for chronic HBV in 2008.
Good bioavailability.
What is the mechanism of ribavirin?
Ribavirin Mechanisms:
(a) favor Th1 vs Th2 response,
(b) Inhibit IMP dehydrogenase and deplete GTP/dGTP pools,
(c) substrate for viral polymerase and may terminate chains,
(d) incorporated into viral genome and acts as a mutagen
What is ribavirin good against?
- Active against RNA and DNA viruses in cell culture
- Active against HCV when given along with interferon alpha
- Used for influenza virus infections
- Used for respiratory syncytial virus infections with and without a monoclonal antibody against RSV
What are some potential sites of anti-HIV therapy?
Cell attachment, fusion, and entry
Reverse transcription
Integration
Transcription and post transcriptional processing
virion packaging and budding
Is reverse transcriptase error free? What are the clinical results of this? What is done to overcome it?
It is very error-prone which means that one individual will likely have many different genotypes of the virus, resulting in some escape viruses.
Therefore, patients should be treated with multiple drugs with multiple mechanisms of action.
What are some inhibitors of HiV?
Enfuvirtide and selzentry( fusion and entry), reverse transcriptase inhibitors (nucleoside analongs and non nucleoside inhibitors), peptomimetic analogs and tepranavir(protease inhibitors), and Raltegravir (Integrase inhibitor)
What are some inhibitors of HIV that block HiV entry into cells? How do they work?
Enfuvirtide (inhibits fusion), selzentry (CCR5 chemokine entry)
What are two types of inhibitors of reverse transcriptase?
Substrate analogues or nucleoside analogs AND non nucleoside inhibitors
How do the substrate analogs work to prevent reverse transcriptase from functioning? What lends them their specificity?
Target the active site of Reverse Transcriptase. Act as competitive inhibitors. Also act as substrates (alternative to dATP, dGTP, dCTP, dTTP)–are incorporated in cDNA, lead to chain termination.
Gain specificity because reverse transcriptase is more likely to incorporate them than dna polymerase is.
How do the non nucleoside inhibitors work to prevent reverse transcriptase from functioning?
They bind allosterically to reverse transcriptase but close to the active site and cause a conformational change resulting in enzyme activity inhibition.
How do most HIV protease inhibitors work? Which kinds of viruses are they good against?
• Peptomimetic compounds
– Mimic the transition state formed by hydrolysis of peptides
– Lack amide bonds, bind to the viral proteases but are not cleaved
• Potentially active against all viruses that encode essential proteases. HIV has 7 sites at which peptide cleavage is required for replication.
How do Inhibitors of HIV cDNA Integration into
Cellular DNA work? How are they used clinically?
•Inhibits function of HIV integrase
•Used in combination therapy for patients with
proven resistance to other HAART drugs
•Escape mutants develop rapidly when used as
monotherapy
What are some strategies used to minimize the emergence of drug resistant mutants?
- Use only when really needed and in adequate amounts
- Use combined therapy- - highly active antiretrovirus therapy (HAART)
- Test isolates during treatment regime
- Save some drugs for only designated diseases or replacement therapy
What is the main combination drug used in first line treatment of HIV? What types of drugs does it consist of? What can be done to know which drugs to use? What drug is used for HIV prevention (prophylactically)?
Atripla is common for first-line treatment (2 NRTIS and 1 NNRTI)
Can sequence genome prior to treatment to determine drug-resistant mutations—then treat accordingly
Clinical trials: Pre-exposure prophylaxis prevents HIV transmission
Truvada approved in 2012 to prevent HIV infection (costly) (combo drug w/ 2 NRTIs)
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