Antiviral drugs Flashcards
(26 cards)
What is a virus?
An infectious, obligate intracellular molecule comprising of genetic material (DNA or RNA) surrounded by a protein coat and sometimes a membrane
Virus infectious cycle (n=5 steps)
- Attachment and entry
- Production of viral mRNA and protein synthesis
- Genome replication
- Assembly and release of viral particles
- Maturation
Productive infection requires ___________ and _________: these are all potential antiviral targets
Viral and host proteins
All viral genomes must be copied to produce _________ that can be read by host ribosomes
mRNA
Baltimore system of classification (n=7)
I. dsDNA II. ssDNA III. dsRNA IV. + ssRNA V. - ssRNA VI. + ssRNA with dsDNA intermediate VII. Gapped dsDNA
Challenges of antiviral development:
Safety: described in terms of ________ index (for cells) and ___________ index (for host)
Potency: even modest reproduction in presence of ____________ provides the opportunity for appearance of ____________ mutants
Cytotoxic; therapeutic
Inhibitors; resistant mutants
Drugs for Herpesvirus infection (n=2)
- Nucleoside and nucleotide analogues (Ribvarin, Acyclovir, AZT)
- Foscarnet
Nucleoside and nucleotide analogues
- Ribvarin: synthetic ______________ analogue. Active against multiple ________ and ________ viruses in vitro. Approved for treatment of ____________ and _______
- Acyclovir: specific ____________ drug. Effective against ____________ virus. Nucleoside analogue related to ______________ and contains _____________ groups.
- AZT: first drug licensed for treatment of ______ infection. An analogue of _______________.
- Guanosine; DNA and RNA; RSV and HCV
- Non-toxic; Herpes simplex; guanosine; acyclic
- HIV; thymidine
Nucleoside drugs activation and mechanism of action:
- Conversion to the ____________ form requires sequential activities of _________ and/or ________ kinases to produce a triphosphate derivative.
- Requirement for viral _________ for activation of the drug provides _____________ to infected cells
- Most agents work by mediating _______________ of DNA synthesis
- Active; viral and/or host
- Kinases; specificity
- Chain termination
Acyclovir and Valacyclovir
- Treatment for __________ and __________
- Not sufficiently active against ________
- Valacylovir is a ______________ with enhanced oral _________________ and is converted to acyclovir by ____________ and _____________ enzymes
- HSV and VZV
- CMV
- Prodrug; bioavailability; intestinal and hepatic
Herpesvirus resistance to Acyclovir and other nucleoside analogue drugs
Cause of resistance: loss of thymidine _________ or any other _________ protein(s)
- Kinase; viral
Foscarnet
- The only non _________ /____________ antiviral against _____________ infection
- Noncompetitive _________ that binds directly to pyrophosphate binding site of catalytic centre of Herpesvirus ________ polymerase
- Doesn’t require activation by _________ or _______ proteins
- Active against: _______ , _________, __________
- Mostly used to treat ________ in patients w/ AIDS, ______________ HSV infections and ____________
- Nucleoside/nucleotide; herpesvirus
- Inhibitor; DNA
- Viral or host
- HSV, VZV, CMV
- CMV; acyclovir-resistant; shingles
Drugs for HIV infection:
- Inhibitors of viral protease:
- Inhibitors of strand transfer:
- Entry inhibitors:
- Squinavir and Darunavir
- Raltegravir and Dolutegravir
- Maraviroc and Enfuvirtide
Saquinavir and Darunavir
- Inhibitory peptide __________-
- Darunavir is a second generation ____________________ for which many mutations in the virus are required to develop ___________
- Mimic
- Peptidase inhibitor; resistance
Raltegravir and Dolutegravir
- Prevents DNA strand ___________ (integration) by binding divalent cations in catalytic core of _________
- Transfer; integrase
Maraviroc and Enfuvirtide
- _____________ inhibitors
- Mechanism:
1. Virus enters via fusion ________
2. Maraviroc binds to ____________
3. Doesn’t bind to viral glycoproteins but targets host proteins
4. Maraviroc is only active against ______________ HIV
- Entry
- Proteins
- Co-receptor
- CCR5-tropic
Mutations in DNA and RNA viruses
RNA viruses:
- Lack of _______________ activity in RdRP
- Average error frequency: in a 10 kb genome, ___ mutation per genome
DNA viruses:
- ______________ activity
- Don’t make as many ___________ as RNA viruses
- Most DNA viruses generate less __________ and evolve ____________ than RNA viruses
- Proofreading
- 1
- Proofreading
- Mistakes/mutations
- Diversity; slower
Combination therapy
Highly active antiretroviral therapy (HAART): multi drug treatment which ___________ viral loads and improves ____________ in HIV-positive individuals
- Combining ___ or more drugs w/ distinct target __________ chance of ___________ virus : genome must carry multiple ___________ to confer resistance
- Mutations appear only when viral genome is ___________. If replication is blocked by an inhibitor, no new drug resistant mutants can __________
- Reduces; survival
- 2; reduces; resistant; mutations
- Replicated; arise
Drugs for Hepatitis C virus (HCV)
- Direct-acting antiviral drugs (DAAs)
- HCV RNA polymerase inhibitor (Sofosbuvir)
- Sofosbuvir can effectively treat genotype 1 to 4 of HCV
- Velpatasvir can effectively treat all 6 genotypes of HCV
HCV infectious cycle and antiviral drugs:
- Due to high ______________ rate of HCV RNA polymerase, the use of _______________ therapy is required
- Combined use of DAAs cures about _____ of patients
- Mutation; combination
- >90%
Drugs for influenza
- Amantadine
- Zanamivir and Oseltamivir: neuraminidase inhibitors
Amantadine:
- Targets influenza A virus _____ protein which forms tetramer that creates ___________________ ion channel that transports protons
- Amantadine binding to outside of tetramer is thought to ___________ entry of __________ allosterically
- Emergence of resistance strain has rendered Amantadine highly _________________
- M2; transmembrane
- Block; protons
- Ineffective
Zanamivir and Oseltamivir
- Block ______________________ which is important for virus _____________ from host cell
- Highly _____________ so given as a last resort
- Neuraminidase; release
- Toxic
Biologics
- Palivizumab
- Interferons
