26 - Antiviral Vaccines and Therapies Flashcards
Examples of antiviral targets
Fusion proteins, proteases, and polymerases
Effective antiviral drugs also have good pharmacological properties
- Whether the drug has side effects
- Whether it can be taken orally
- How long it persists in the human body
- How the human body breaks down or otherwise modifies the drug
Challenges to development of effective antiviral agents
- Viruses replicate intracellularly
- Some viruses establish latent infections (treating active infection does not cure disease)
- Different viruses (especially respiratory viruses) cause similar symptoms, making diagnosis difficult
- Generation of drug resistance
HIV RT
Heterodimer composed of 2 subunits (p66 and p51)
Nucleoside RT inhibitors (NRTIs) binding site
Bind at the Pol active site
Non-nucleoside RT inhibitors (NNRTIs) binding site
Bind in a nearby hydrophobic binding pocket
Nucleoside Reverse Transcriptase Inhibitors (NRTIs)
- Competitive inhibitors of viral polymerases (including HIV RT)
- Compete with natural dNTP/NTP substrates for incorporation into the nascent viral nucleic acid, and so act as chain terminators
AZT
- Azido (NH3) group on the ribose instead of a hydrogen
- DNA synthesis blocked
Resistance to NRTIs
- Emergence of discriminatory mutations
- Allow viral RT to preferentially select naturally occurring deoxynucleotides present in the cell
Non nucleoside RT inhibitors
- Bind to p66 subunit at a hydrophobic pocket distant from the active site of the enzyme, causes conformational change that alters active site
- Useful in combination with other drugs
- E.g Nevirapine used to reduce transmission from mother to child during birth
How do second gen NNRTIs differ from first gen
In its ability to bind at this site despite the presence of some mutations that limit the efficacy of first-generation agent
2 catalytic reactions of proviral integration
- 3’-processing in the host-cell cytoplasm to prepare proviral strands for attachment
- Strand transfer whereby proviral DNA is covalently linked to cellular DNA
INSTIs (Integrase Inhibitors)
Competitively inhibit the strand transfer reaction by binding metallic ions in the active site
Fusion inhibitors
- First class of antiretroviral medications to target HIV replication cycle extracellularly
- Fusion inhibitors act extracellularly to prevent fusion of HIV to the CD4 molecule
Medication ending in ‘mab’
Monoclonal antibody
Post attachment inhibitors
Bind to domain2 (D2) of CD4 and prevent normal structural, conformational change required for attachment
Resistance to CCR5 antagonist
Occur when R5 tropic HIV 1 develops mutations that facilitate gp120-CCR5 binding despite Maravirox attachment to CCR5
Protease inhibitors
Competitive inhibitors that bind directly to HIV-1 protease catalytically active site and prevent cleavage of polypeptides
Virologic rebound
Defined as confirmed detectable HIV RNA (greater than 200 copies/mL plasma) after virologic suppression
Reemergence of wild type HIV after ceasing antiretroviral therapy
- Discontinuation of the antiretroviral therapy regimen will remove the selective pressure on HIV
- Reversion to wild type virus
- WT virus may have greater replicative fitness than mutant , drug resistant virus
- Growth of WT virus may outpace resistant virus reemergence of a largely WT population
Drugs for HSV and VZV
- Oral agents (e.g. Acyclovir)
- Opthalmic
- Topical agents
Acyclovir mechanism of action
- Guanosine analog that is active against herpesviruses
- Taken up by herpesvirus-infected cell
- Viral encoded thymidine kinase (TK) phosphorylates to ACV monophosphate
- Cellular enzymes convert to ACV triphosphate
- HSV TK selectively phosphorylates guanosine analogs such as ACV
- Inhibits function of viral DNA polymerase (analogs act as DNA chain terminators)
What is acyclovir active against
Active against HSV-I; HSV-2; VZV
Gancyclovir
- Acyclic analog of the nucleoside guanosine
- Inhibits viral DNA polymerases more than cellular DNA polymerases
Influenza agents
Amantadine
Amantadine
Target IVA M2 protein ion channel
Function of M2 protein ion channel
- Derived from host cell
- Dissociation of influenza virus RNA from ribonuclear proteins (by acidification of virion interior via M2)
Zanamivir and Oseltamivir
- NA inhibitors
- Analogs of sialic acid
Passive immunisation
Immune globulins (e.g. HBV immune globulin)
Key to global control of viral infections
Vaccination
