Antivirals Flashcards
What are the 8 antiviral classes?
Adamantanamines Neuraminidase inhibitors Interferons Nucleoside/nucleotide antimetabolites Reverse transcriptase inhibitors Protease inhibitors Integrase inhibitors Cell entry inhibitors
What are the 7 stages of viral infection?
Absorption (attachment to receptors) Penetration (entry) Uncoating (release of viral nucleic acid) Transcription Translation Assembly Release
What is the MOA of adamantanamines
They interfere with the penetration of host cells by viruses and block early stage replication (uncoating). They also affect a later step involved in viral assembly
What are some adamantanamines?
Amantadine
Rimantadine
What are some neuraminidase inhibitors?
Zanamivir (Relenza) - inhaled powder
Oseltamivir (Tamiflu) - oral (ethyl ester allows oral bioavailability)
What is the MOA of Zanamivir? What is key for this?
It inhibits neuraminidase by binding to the active sialic acid-sugar bond cleavage
Guanidine group is key for competitive inhibition
What is the key for oseltamivir?
Non-polar 3-pentyl group is key for maximum binding
What are interferons?
Extremely potent cytokines that possess antiviral, immunomodulating and anti proliferative actions
What are the antiviral effects of interferons?
Inhibition of:
- viral penetration or uncoating
- mRNA synthesis
- translation of viral proteins (protein synthesis inhibition predominates)
- viral assembly and release
What interferons do we use clinically?
IFN-alpha is used clinically in recombinant form
IFN-beta (Betaseron) is used for the treatment of MS
IFN-alpha-2b (Intron A) is used for chronic Hep C
What are acyclovir and valacyclovir?
Nucleoside antimetabolites with potent activity against several DNA virus (HSV-1, HSV-2)
Valacyclovir is a prodrug of acyclovir that is metabolized into acyclovir in vivo
What is the MOA of acyclovir and valcyclovir??
They are synthetic analogous of deoxyguanosine, where the carbohydrate moiety is acyclic (a straight chain, not a cyclic sugar)
When this analogue is incorporated into viral DNA, the lack of sugar terminates elongation
What is adefovir dipivoxil
It is a competitive inhibitor for HBV reverse transcriptase (adenosine analogue; chain terminator) for the treatment of chronic hepatitis B
It is a prodrug; metabolized into adefovir (PMEA)
What are ganciclovir and penciclovir?
They are analogues of acyclovir, with an additional hydroxymethyl side chain
This modification increase their activity against CMV
What is the MOA of ganciclovir?
It is phosphorylated inside the host cell then is incorporated into DNA (stops elongation)
What is the MOA of penciclovir?
It is phosphorylated by viral thymidine kinase and competitively inhibits DNA elongation
What is Cidofovir?
Acyclic pyrimidine nucleotide analogue of cytosine, metabolized in vivo to active diphosphate. It inhibits viral replication via DNA synthesis interference
What are cytarabine and idoxuridine?
Synthetic pyrimidine analogs of cytidine and uridine, respectively, and are metabolically converted to active triphosphate and incorporated into DNA during replication
Cytarabine blocks utilization of deoxycytidine
Idoxuridine replaces thymidine (faulty viral proteins)
What is ribavirin?
(IBAVYR)
A guanosine anaolgue, with broad spectrum antiviral activity, both DNA and RNA
Phosphorylated by adenosine kinase and inhibits viral RNA polymerase
What is trifluorotymidine?
Fluorinated analog of thymidine with triphosphate incorporated into viral DNA in place of thymidine giving faulty viral mRNA proteins
What is vidarabine?
An adenosine nucleoside analog, with the triphosphate interfering with viral nucleic acid replication due to arabinose sugar (not ribose)
What is sofosbuvir (Sovaldi)?
It is a uridine nucleotide analogue used in combination with other drugs (ledipasvir) for the treatment of hepatitis C infection
What is the MOA of sofosbuvir?
It inhibits the RNA polymerase that the Hep C virus uses to replicate its RNA
It is a prodrug that is metabolized into a triphosphate and that serves as a defective substrate for the viral RNA polymerase
What are the 3 activities of reverse transcriptase?
RNA-dependent DNA polymerase
Ribonuclease H (enzyme catalyzes cleavage of RNA)
DNA-dependent DNA polymerase
What was the first NRTI?
Azidothymidine (AZT) for HIV
The azido group increases the lipophilic nature
What are some other NRTIs?
Abacavir (ABC) Didanosine (ddI) Emtricitabine (FTC) Lamivudine (3TC) Stavudine (d4T) Tenofovir DF (TDF)
What are some combination NRTIs?
Abacavir and lamivudine (Epicom)
Zidovudine and lamivudine (Combivir)
Tenofovir and emtricitabine (Truvada)
Zidovudine, lamivudine, abacavir (Trizivir)
What is the MOA of tenfovir (PMPA)?
PMPA needs to be phosphorylated, in one or two steps, to the diphosphate form
It then interferes with the reverse transcriptase reaction
How do NNRTIs differ from NRTIs?
They do not require bioactivation by kinases to give phosphate; they are not incorporated into DNA chain
They bind to an allosteric site that is distinct from the substrate binding site of RT
They exhibit classical non-competitive inhibition pattern
What are the 3 big NNRTIs?
Nevirapine
Delavirdine
Efavirenz
How does resistance to NRTIs and NNRTIs occur?
HIV-1 RT does not have proof-reading activity and therefore mutations can develop rapidly. Selective pressure from the drug leads to mutations in RT that make the virus less susceptible to NRTIs and NNRTIs
Where do mutations in RT occur?
Residues in the RT polymerase domain that are important in the binding and incorporation of nucleotides
The side chains of residues that interact with the next incoming nucleotide
Residues which interact with the template strand to position it for base pairing with the nucleotide. Mutation of these key amino acids results in reduced incorporation of the analogues
What are some first generation protease inhibitors?
Saquinavir (Invirase) Indinavir (Crixivan) Ritonavir (Norvir) Amprenavir (Agenerase) Nelfinavir (Viracept
What are some second generation protease inhibitors?
Lopinavir (usually with ritonavir)
Atazanavir (always with an RT inhibitor)
Tipranavir (peptidomimetic)
Darunavir (has a bis-tetrahydrofuranyl moiety)
What is at the centre of protease inhibitors?
A phenylalanine-hydroxyl sp3-tetrahedral transition state
What is retroviral integrase? What are integrase inhibitors?
It enables the genetic material of the retrovirus to be integrated into the DNA of the infected cell; Integrase inhibitors block strand transfer catalyzed by retroviral integrase enzyme
What are some integrase inhibitors?
Raltegravir
Elvitegravir
What is the MOA of raltegravir?
It binds to viral integrase and prevents the DNA transfer function that inserts the viral DNA into host DNA
What must integrase inhibitors contain for function and why?
Inhibitors must contain a dicarbonyl functional group for activity, for metal binding and strand transfer
They also require a benzyl moiety to bind hydrophobic pocket, a HHCC zinc-finger and a DDE Mg/Mn (these are essential for binding)
What are some CCR5 antagonists?
Maraviroc (Celsentri; only approved one)
Vicriviroc
PRO 140
What are some CXCR4 inhibitors?
AMD-11070
What is the MOA Of Maraviroc?
It binds to CCR5, blocking HIV gp120 association and entry
What is an HIV fusion inhibitor?
Enfuvirtide (Fuzeon)
It binds to gp41 preventing creation of entry pore for the capsid of the virus
