Lecture 21 - Antiviral agents Flashcards
What is a virus?
A small infectious agent that must invade a living cell to reproduce
Examples of viral diseases
Influenza, AIDS, chickenpox, cold sores, rabies, hepatitis, pneumonia, SARS, COVID-19, MERS, ebola
Baltimore classification of viruses -
Class 1
- dsDNA (+/-)
- Herpes virus, poxvirus, adenovirus, papilllomavirus
Baltimore classification of viruses -
Class 2
- ssDNA (+)
- Adeno-associated virus
- Must be transcribed into dsDNA before mRNA
Baltimore classification of viruses -
Class 3
- dsRNA (+/-)
- Reovirus
Baltimore classification of viruses -
Class 4
- (+) ssRNA
- Togavirus, poliovirus, foot-and-mouth disease virus, Hep A, Hep C
- Can be translated directly into protein
Baltimore classification of viruses -
Class 5
- (-) ssRNA
- Influenza virus
- Must have gemone copied by an RNA replicase to form positive-sense RNA
Baltimore classification of viruses -
Class 6
- (reverse) ssRNA
- HIV
Baltimore classification of viruses -
Class 7
- (reverse) dsDNA
- Hep B virus
- Replicate via ssRNA intermediate
What cells does HIV infect?
CD4+ cells
Basic steps of HIV life cycle
- Viral attachment
- fusion to CD4+ cell
- Reverse transcription of viral RNA into DNA
- Integration of DNA into host nucleus
- Transcription and translation of normal and viral mRNA
- Virion assembly and budding
- Maturation of protease
What are the most common targets of antiviral agents?
Differences between the structures and functions of viral and human proteins or focus targets that are not essential fr the host but critical for the virus
Viral life cycle
- Attachment and entry into cell
- Uncoating of RNA or newly synthesized mRNA
- Protein synthesis using host ribosomes
- Post-translational processing and genome replicaton
- Assembly and maturation
- Egress and release from host cell
What class of drugs are used to prevent viral attachment and entry?
Attachment and entry inhibitors
What class of drugs inhibits viral uncoating?
Ion channel blockers
What class of drugs inhibits post-translational processing of viral proteins?
NS3/4A inhibitors
What classes of drug inhibits viral genome replication?
Polymerase inhibitors, NSSA inhibitors, Intergrase inhibitors
Whar class of drugs inhibits viral assembly?
HIV protease inhibitors
What class of drug inhibits excretion of viral agents?
Neuraminidase inhibitors
Inhibition of viral attachment and entry
What is Maraviroc?
A small-molecule negative allosteric modulator of the CCR5 chemokine receptor
- Blocks cellular infection of HIV that use CCR5 for attachment and entry
Inhibition of viral attachment and entry
What is Enfuvirtide (T-20)?
A synthetic peptide drug that mimics HR2, binds to HR1, and prevents HR2-HR1 interaction
- Drug traps the virus-host cell interaction at the attachment stage, preventing membrane fusion and viral entry
What is an allosteric modulator?
A drug that binds to a receptor at a site distinct from the active site. Induces a conformational change in the receptor, which alters the affinity of the receptor for the endogenous ligand.
- Positive allosteric modulators increase the affinity
- Negative allosteric modulators decrease the affinity
Affects affinity or potency, antagonists affect efficacy
Inhibition of viral uncoating
Amantadine and rimantadine
Block M2 proton channel function –> inhibits acidification of the interior of the virion, matrix protein dissociation, and uncoating (low pH promotes uncoating and virion release)
- Used to treat influenza
- Amantadine also treats parkinsonism, a weak antagonist of the NMDA receptor, increases dopamine release, and blocks dopamine reuptake.
Inhibition of viral gene expression (posttranslational protein cleavage)
Simeprevir, Telaprevir, Boceprevir, Paritaprevir
Anti-HCV protease inhibitors that cleaves the Hepatitis C virus polyprotein
- Sites of cleavage: viral NS2 protease, viral NS3/4A protease
- All four drugs inhibit viral HCV NS3/4A protease with higher potency than they do human proteases
