Antiviral drugs Flashcards
Nucleotide and nucleotide analogies mode of action
They must be activated by phosphorylation to exert their effect. Phosphorylated nucleoside analogues inhibit polymerase by competing with the natural substrate (dNTP) to cause chain termination.
They are used against herpesvirus, HIV, and HBV.
Acyclovir (nucleoside analogue)
Used to treat: herpesvirus 1+2 and varicella zoster virus.
MOA: inhibits DNA synthesis in three steps:
1. Competitive competition (dGTP) – viral DNA polymerase..
2. Chain termination upon incorporation into DNA.
3. Freeze viral polymerase.
The viral thymidine kinase is 3000x more effective than the cellular thymidine kinase, so ACV uses the viral thymidine kinase to be converted to its active form (pppACV).
OBS: only works in virus-infected cells because it relies on the viral DNA polymerase; it has a much higher affinity for this enzyme than for cellular DNA polymerase. (It does not work in latent herpes virus, because it requires an active DNA polymerase).
Unwanted effects: minimal, local inflammation (i.v.), renal dysfunction (a slow infusion reduces risk).
Ganciclovir (nucleoside analogue)
Used to treat: human cytomegalovirus.
MOA: inhibits DNA synthesis by:
1. Compepetite competition (dGTP) – viral DNA polymerase.
2. Chain termination upon incorporation into DNA:
Unlike herpes, human cytomegalovirus does not encode viral thymidine kinase. It is phosphorylated by viral enzymes and then by cellular enzymes so that the drug can become activated. Then, it gets incorporated and can stop polymerase activity.
Very similar to acyclovir in that it only targets virus infected cells.
To treat HIV which drug can be used?
- Reverse transcriptase inhibitors such as Zidovudine and Tenofovir.
- Non-Nucleoside reverse transcriptase inhibitors such as Efavirenz and Nevirapine.
- HIV integrase inhibitors with drugs such as Raltegravir.
- Protease inhibitors such as Ritonavir.
- Inhibition of viral attachment and entry with Maraviroc or Enfuvirtide.
Zidovudine /azidothymidine (AZT) (Reverse transcriptase inhibitors, nucleoside analogue).
Used to treat HIV.
MOA: HIV does not encode kinases; AZT is an excellent substrate for the cellular thymidine kinase. AZT targets the reverse transcriptase (RT). AZT is more potent in targeting viral RT than the cellular DNA polymerase. DNA chain termination – the precise mode of action is not entirely solved, but comparable to acyclovir and ganciclovir.
Meant to target reverse transcriptase, but there is poor selectivity because it is activated by cellular thymidine kinase and can act in all host cells.
Unwanted effects: GI disturbance, blood disorders, CNS effects.
Tenofovir (Reverse transcriptase inhibitors, nucleotide analogue).
Used to treat HIV.
Nucleotide analogue of adenosine that acts as an inhibitor of the viral RT
Also used in the treatment of hepatitis B (Recall: HBV also uses a RT); however, HBV patients must be tested for HIV prior to treatment because Tenofovir can introduce mutations in HIV-RT
Nonnucleoside reverse transcriptase inhibitors
Used to treat HIV.
These drugs inhibit the viral target directly, without the need for chemical modification. They bind to the reverse transcriptase enzyme near the catalytic site and inactivate it.
Efavirenz (Nonnucleoside reverse transcriptase inhibitors)
Used to treat HIV.
Low genetic barrier for resistance
o Combination therapy with tenofovir, emtricitabine (FTC; nucleoside analog) and efavirenz
o MOA: X-ray crystallographic studies showed that NNRTI bind near the catalytic side of the RT and thereby block the enzyme by an allosteric mechanism
o Neuropsychiatric side effects since Efavirenz is a ligand for 5-HT receptors
o 99% protein plasma bound, so low penetration into the CSF
Nevirapine (Nonnucleoside reverse transcriptase inhibitors)
o Good bioavailability, penetrates into the CSF
o Can prevent mother-to baby transmission of HIV
o Unwanted effects: dermatological effects, GI disturbances, CNS and related effects, musculoskeletal and blood disorders and metabolic effects.
Raltegravir (HIV integrase inhibitors)
MOA: Strand transfer inhibitor. Integration of linear dsDNA into the host genome. The catalytic core of the enzyme includes three conserved aa residues (DDE motif). Raltegravir binds to the DDE motif and with additional moieties to the enzyme – inhibits the interaction of the enzyme with the Mg2+.
Protease inhibitors
For many viruses, including HIV, the assembly of proteins and nucleic acid into particles is not sufficient to produce an infectious virion. An additional step is required (maturation) and virus encoded protease is essential for this step. Protease inhibitors inhibits this.
Ritonavir (Protease inhibitors)
MOA: Competes with the active cleavage site on the protease. This blocks the cleavage of the polyprotein – virus maturation.
Resistance: accumulation of multiple protease inhibitor-resistance mutations
e.g. binding affinity between the inhibitor and the protease enzyme -> alteration in the enzyme catalysis.
Not used in high enough doses to inhibit the HIV virus particle production but inhibits the P450 enzyme that degrades this class of medications, so it is often used in combination with other protease inhibitors.
Unwanted effects: gastrointestinal disturbances (e.g. nausea, vomiting, abdominal pain), blood disorders, sometimes anemia or neutropenia, CNS effects, insomnia, dizziness. headache
Maraviroc (inhibition of viral attachment and entry)
Entry inhibitor. Maraviroc binds CCR5 (but not CXCR4) and thereby blocks the HIV envelope protein gp120 from associating with CCR5.
This is beneficial because CXCR4 KO is lethal
Maraviroc is active against CCR5 tropic viruses but not against HIV strains that use a different co-receptor (i.e. CXCR4)
In HIV-infected individuals, CXCR4-using HIV1 strains increase with disease progression and decrease in CD4 T cell counts.
Enfuvirtide (inhibition of viral attachment and entry)
MOA: Binds to the region of the gp41 subunit of the HIV-1 envelope. This inhibits the conformational change of gp41 that is required for viral and host-cell membrane fusion. The conformation change is essential to bring the viral and cellular membrane in close enough proximity for fusion, thus there is no virus entry
