Antivirals 1 Flashcards
What are the antivirals for herpes viruses?
acyclovir, valacyclovir, penciclovir, famciclovir, ganciclovir, valganciclovir, foscarnet, cidofovir, letermovir
What is the MOA of acyclovir?
acyclic guanosine derivative; competitive inhibitor of viral DNA polymerase, competes with dGTP, competition occurs at a lower concentration for viral DNA polymerase than host polymerase; DNA polymerase becomes bound to template irreversibly; acyclovir is incorporated into DNA and acts as chain terminator (can’t replicate viral genome)
Selectively accumulates in infected cells resulting in higher concentration in infected cells (high ratio of therapeutic value to toxicity) because it is phosphorylated by viral thymidine kinase
Acyclovir resistance
can develop by two mechanisms: mutations in viral thymidine kinase (can’t phosphorylate acyclovir triphosphate well) or mutations in viral DNA polymerase (can’t accommodate drug effectively in active site)
What is the spectrum of activity of acyclovir?
HSV-1, HSV-2, and VZV; reduced activity against CMV
What is the MOA of valacyclovir?
L-valyl ester of acyclovir, rapidly converted to acyclovir by esterases in the intestine and liver; transported by intestinal amino acid transporters (dipeptide transporter)
same MOA, resistance, and spectrum of activity as acyclovir
What is the MOA of penciclovir?
activated by viral and cellular kinases; competitive inhibitor of viral DNA polymerase; does NOT cause immediate chain termination, allows for short chain elongation
o Penciclovir has higher affinity for HSV TK than acyclovir so levels of penciclovir triphosphate in infected cells are much higher than the levels of acyclovir triphosphate, also more stable
o HSV DNA polymerases have higher affinity for acyclovir triphosphate than for penciclovir triphosphate
o Net effect: both drug have similar antiviral potencies
What is the spectrum of activity of penciclovir?
recurrent herpes labialis
What is the MOA of famciclovir?
prodrug of penciclovir, lacks intrinsic antiviral activity; same as penciclovir
What is the spectrum of activity of famciclovir?
primary and recurrent genital herpes, acute herpes zoster
What is the MOA of ganciclovir?
same as penciclovir
Resistance in ganciclovir
due to mutations in CMV kinase (UL97 gene) or CMV DNA polymerase (UL54); mutations in kinase are not cross-resistant to cidofovir or foscarnet
What is the spectrum of activity of ganciclovir?
better substrate for CMV kinase than acyclovir; IV, oral and intraocular implants for CMV retinitis; oral can be used for CMV prophylaxis
What is the MOA of valganciclovir?
monovalyl ester of ganciclovir; rapidly hydrolyzed to ganciclovir by esterases in intestine and liver
What is the spectrum of activity of valganciclovir?
CMV retinitis in AIDS patients
What is the MOA of foscarnet?
inorganic pyrophosphate compound that inhibits viral DNA polymerase, RNA polymerase, and HIV RT; does NOT require phosphorylation for activity; blocks pyrophosphate binding site of the viral DNA polymerase and inhibits cleavage of pyrophosphate form dNTPs (not able to have new base added to DNA growing chain)
o Carboxyl overlaps with binding site of beta-phosphate; phosphonates occupies position of gamma-phosphate; traps polymerase in closed formation; DNA is unable to translocate
Foscarnet resistance
mutations in DNA polymerase or HIV RT; resistant CMV isolates are cross-resistant to ganciclovir, usually still effective against cidofovir resistant CMV
What is the spectrum of activity of foscarnet?
CMV retinitis; synergistic with ganciclovir against CMV
What is the MOA of cidofovir?
Acyclic nucleoside phosphonate analog of cytosine, phosphonate cannot be cleaved by cellular esterases – catabolically stable; phosphorylated by cellular kinases (only need 2 phosphorylation’s for it to be active)
o Poor substrate for cellular (human) DNA polymerase – selective toxicity in inhibiting DNA polymerase form virus and not inhibiting DNA polymerase form human cells; highly selective for viral DNA pol
o Does NOT require activation by viral kinases
What is the spectrum of activity of cidofovir?
CMV retinitis is the main one; HSV-1/2, VZV
What is the MOA of letermovir?
non-nucleoside; highly specific for CMV; low nanomolar EC50 (at low concentration can inhibit virus replication)
o Herpes virus DNA replication is through rolling circle mechanism: produces concatemers, individual genomes must be cut out by “terminase complex”- 3 different enzymes in CMV that come together to function to cut out the DNA for the virus: pUL56, pUL89, pUL51
o Letermovir inhibits terminase complex – binds to pUL56, prevents cleavage and packaging, no effect on protein synthesis or DNA replication
Letermovir resistance
NO cross resistance to other CMV drugs
What is the spectrum of activity of letermovir?
prophylaxis of CMV infection and disease in adult allogeneic hematopoietic stem cell transplant (HSCT) patients who have CMV
Which drugs are DNA chain terminators?
acyclovir, valacyclovir, cidofovir, ganciclovir, valganciclovir, famciclovir, penciclovir
Which drug are incorporated into DNA?
acyclovir, valacyclovir, ganciclovir, valganciclovir, cidofovir, famciclovir, penciclovir
Which drugs are pro-drugs?
valacyclovir, famciclovir, valganciclovir
Which drugs can cause cross-resistance?
o Famciclovir and penciclovir: viral kinase mutants confer cross-resistance to penciclovir and acyclovir
o Ganciclovir: mutations in DNA polymerase may confer resistance to cidofovir or foscarnet
Describe the binding site of foscarnet on DNA polymerase
o Carboxyl overlaps with binding site of beta-phosphate on triphosphate nucleotide; phosphonates occupies position of gamma-phosphate; traps polymerase in closed formation; DNA is unable to translocate
Why are foscarnet-resistant viruses likely to be cross-resistant to gangciclovir?
o Foscarnet-resistant viruses are often cross-resistant to ganciclovir because resistance to both drugs typically involves mutations in the viral DNA polymerase (UL54) rather than the viral thymidine kinase (UL97).
Why are viral thymidine kinase mutants resistant to ganciclovir and not resistant to cidofovir or foscarnet.
o Ganciclovir requires phosphorylation by viral thymidine kinase (or a similar viral kinase, such as UL97 in cytomegalovirus) to become its active form, ganciclovir triphosphate. Mutations in the viral TK gene prevent this phosphorylation, leading to resistance.
o Cidofovir, on the other hand, does not rely on viral kinases for activation. It is a nucleotide analog that is already phosphorylated to its monophosphate form. Cellular kinases then convert it to its active diphosphate form, which inhibits viral DNA polymerase. Since its activation is independent of viral TK, it remains effective against TK-resistant viruses.
o Foscarnet also bypasses the need for activation by viral kinases. It directly inhibits viral DNA polymerase by binding to its pyrophosphate binding site, blocking the enzyme’s ability to incorporate nucleotides into the viral DNA. This mechanism makes it effective against ganciclovir-resistant strains with TK mutations.
How is cidofovir metabolized to form the biologically active species?
o Cidofovir is a cytosine nucleotide analog that requires phosphorylation to become its biologically active form. It does not rely on viral kinases for activation. Instead, it undergoes a two-step phosphorylation process by host cellular kinases:
o Initial phosphorylation: Cidofovir is already a monophosphate nucleotide analog, meaning it has a phosphate group attached. Cellular kinases (primarily nucleotide kinases) add a second phosphate group, converting it into cidofovir diphosphate (CDV-DP). Cidofovir diphosphate (CDV-DP) is the biologically active form. It acts as a competitive inhibitor of viral DNA polymerase, preventing the incorporation of natural nucleotides into the viral DNA chain. Additionally, it can cause chain termination during viral DNA synthesis. Cidofovir’s ability to bypass viral kinase activation makes it effective against thymidine kinase-deficient or DNA polymerase-mutant viruses, such as those resistant to ganciclovir or foscarnet.
Why do valacyclovir and valganciclovir have greater bioavailability than acyclovir and ganciclovir?
o Valacyclovir and Valganciclovir: have hydrophobic modifications (more lipophilic) that change the drug structure to increase bioavailability by allowing it to pass through the intestinal wall better
What is the influenza virus life cycle?
o Attachment and entry: The virus attaches to host respiratory epithelial cells using its hemagglutinin (HA) protein, which binds to sialic acid receptors on the cell surface internalized via endocytosis into endosome
o Uncoating: The acidic environment of the endosome triggers the activation of the viral M2 ion channel, allowing hydrogen ions to enter the virus. This acidification disrupts the viral envelope, leading to the release of viral ribonucleoproteins (vRNPs) into the cytoplasm.
o Replication and transcription: The vRNPs are transported into the nucleus, where the viral RNA-dependent RNA polymerase transcribes viral RNA into mRNA.
o Protein synthesis and assembly: Viral mRNAs are translated into proteins using the host cell’s machinery. The newly formed viral proteins and RNA genomes are assembled into new virions in the cytoplasm.
o Budding and releasing: The newly assembled virus particles bud from the host cell membrane. The viral neuraminidase (NA) enzyme cleaves glycolytic bonds between sialic acid residues to release the virus and prevent it from clumping at the cell surface.
What are the neuraminidase inhibitors used in influenza?
oseltamivir, zanamivir, peramivir – prevents the cleavage of the receptor, and prevents liberation of virions from host membrane; decrease in viral load that can spread from cell to cell
What is the polymerase inhibitor used in influenza?
baloxavir marboxil
What is the MOA of baloxavir?
inhibits viral “cap-snatching” (blocks transcription); binds to PB2 subunit of RNA polymerase of virus and inhibits the influenza cap-dependent endonuclease; viral mRNAs can no longer be produced
What is the MOA of oseltamivir?
prodrug converted to active form by liver esterases; biologically active metabolite inhibits NA, the 3-pentyloxy structure increases affinity to bind neuraminidase; inhibits neuraminidase enzyme on surface of influenza viruses, preventing release of new influenza virus particles form infected cells
Resistance in oseltamivir
associated with mutations in the active site of neuraminidase; resistance develops more easily against oseltamivir than zanamivir because oseltamivir has more floppy orientation of interactions and zanamivir can still bind and activate the neuraminidase that has these mutations because it fits better in the pocket
What is the MOA of zanamivir?
same as oseltamivir, inhibits neuraminidase enzyme on surface of influenza viruses, preventing release of new influenza virus particles form infected cells; not a prodrug; administered via oral inhaler
Resistance in zanamivir
associated with mutations in the active site of neuraminidase
What is the MOA of peramivir?
given IV; transition state analog of sialic acid; ; inhibits neuraminidase enzyme on surface of influenza viruses, preventing release of new influenza virus particles form infected cells
What is the hepatitis C virus life cycle?
receptor-mediated binding and endocytosis release of viral RNA translation of viral RNA to generate HCV polyprotein proteolytic processing of HCV polyprotein formation of replication complex viral RNA replication virion assembly transport and release of HCV lipoviroparticle; HCV makes single polyprotein that is cleaved by viral and cellular proteases (NS3)
What steps of the cycle are targeted by anti-HCV drugs?
NS5A inhibitors: inhibits formation of replication complex
NS5B polymerase inhibitors: inhibits viral RNA replication
HCV protease inhibitors: target HCV protease NS3, blocking cleavage of HCV polyprotein
What is the hepatitis B virus life cycle?
viral genome replication includes an RNA intermediate that is converted to viral DNA by reverse transcriptase
What are the NS5A inhibitors?
daclatasvir, ledipasvir, elbasvir, velpatasvir, pribrentasvir
What are the NS5B polymerase inhibitors?
sofosbuvir
What are the HCV protease inhibitors?
grazoprevir, voxilaprevir, glecaprevir
Ribavirin: MOA, resistance, and SOA
o MOA: guanosine analog with incomplete purine ring; phosphorylated by cellular kinases to triphosphate form; inhibits inosine monophosphate dehydrogenase (IMPDH) – reduces GTP levels (starves viral replication); get direct inhibition of viral RNA polymerases and incorporation into viral RNA leading to error catastrophe
o Resistance: mutations in NS3 active site
o Spectrum of activity: influenza A and B, hepatitis A, B, C, genital herpes, herpes zoster, measles, hantavirus, lassa fever virus
Grazoprevir: MOA, resistance, and SOA
o MOA: targets the HCV protease NS3 blocking cleavage of HCV polyprotein; ketoamide reversible covalent inhibitor; traps HCV active site and changes active site structure, can no longer accommodate substrate, active site in enzyme structure changes and induces fit around the drug
o Resistance: mutations in NS3 active site
o Spectrum of activity: hepatitis C
Voxilaprevir: MOA, resistance, and SOA
o MOA: targets the HCV protease NS3 blocking cleavage of HCV polyprotein; ketoamide reversible covalent inhibitor; traps HCV active site and changes active site structure, can no longer accommodate substrate, active site in enzyme structure changes and induces fit around the drug
o Resistance: mutations in NS3 active site
o Spectrum of activity: hepatitis C
Glecaprevir: MOA, resistance, and SOA
o MOA: targets the HCV protease NS3 blocking cleavage of HCV polyprotein; ketoamide reversible covalent inhibitor; traps HCV active site and changes active site structure, can no longer accommodate substrate, active site in enzyme structure changes and induces fit around the drug
o Resistance: mutations in NS3 active site
o Spectrum of activity: hepatitis C
Sofosbuvir: MOA, resistance, and SOA
o MOA: NS5B = HCV RNA polymerase inhibitor; prodrug converted to monophosphate by liver enzymes; triphosphorylated by cellular nucleotide kinases: uridine-cytidine monophosphate kinase (YMPK), nucleoside diphosphate kinase (NDPK)
o Incorporated in viral RNA chain, causes chain termination – 2’ methyl group is critical to blocking chain elongation
o Resistance: single mutation in active site (S288T)
o Spectrum of activity: hepatitis C
Ledipasvir: MOA, resistance, and SOA
o MOA: HCV NS5A inhibitor; binds tightly to NS5A and inhibits both viral RNA replication and assembly or release of infectious viral particles
o Resistance: mutations occur in 1st 100 amino acids
Elbasvir: MOA, resistance, and SOA
o MOA: HCV NS5A inhibitor; binds tightly to NS5A and inhibits both viral RNA replication and assembly or release of infectious viral particles
o Resistance: mutations occur in 1st 100 amino acids
Dasabuvir: MOA, resistance, and SOA
o MOA: non-nucleoside RNA polymerase inhibitor; bind and inhibits NS5B (catalytic site); binds to distant site and blocks activity of polymerase (4 allosteric sites)
o Binds to palm I site of HCV RNA polymerase prevents conformational changes blocks nucleotide incorporation into viral RNA
o Spectrum of activity: hepatitis C
Daclatasvir: MOA, resistance, and SOA
o MOA: HCV NS5A inhibitor; binds tightly to NS5A and inhibits both viral RNA replication and assembly or release of infectious viral particles
o Resistance: mutations occur in 1st 100 amino acids
Velpatasvir: MOA, resistance, and SOA
o MOA: HCV NS5A inhibitor; binds tightly to NS5A and inhibits both viral RNA replication and assembly or release of infectious viral particles
o Resistance: mutations occur in 1st 100 amino acids
Pibrentasvir: MOA, resistance, and SOA
o MOA: HCV NS5A inhibitor; binds tightly to NS5A and inhibits both viral RNA replication and assembly or release of infectious viral particles
o Resistance: mutations occur in 1st 100 amino acids
What are the HBV inhibitors:
lamivudine: incorporated into viral DNA, causes DNA chain termination; pro-drug
entecavir: incorporated into viral DNA, causes DNA chain termination; pro-drug
tenofovir: pro-drug converted to tenofovir, only requires 2 phosphorylations; acyclic nucleoside phosphonate analog of adenosine; phosphonate cannot be cleaved by cellular esterases, catabolically stable
How is ribavirin like the NRTIs? Would any NRTIs be expected to compete with ribavirin? If so, how?
- Similar in that it is a nucleoside analog and works through similar mechanisms as NRTIs.
- Both NRTIs and ribavirin require intracellular phosphorylation to their active triphosphate forms.
- Cellular kinases that are responsible for phosphorylating nucleoside analogs are non-specific, meaning they could potentially convert both NRTIs and ribavirin to their active forms.
- If both ribavirin and NRTIs are used together, interference in nucleotide metabolism could occur, potentially affecting the ability of both to inhibit their respective viral targets.
What is the black box warning for HCV direct acting antivirals?
hep B virus reactivation has occurred in patients co-infected with hepatitis C virus while undergoing treatment with direct antivirals for HCV infection; some resulted in fulminant hepatitis, hepatic failure, and death; observed with DAAs used without interferon
What is used for the treatment of SARS-CoV-2?
remdisivir, nirmatrelvir, molnupiravir
What is the MOA of remdisivir?
tri-phosphorylated to active form remdesivir triphosphate, resembles ATP and competes with ATP for incorporation into growing viral RNA chain; causes premature termination of viral RNA synthesis by delaying chain elongation
o Prodrug/metabolism: prodrug that is bio-transformed to a ribonucleotide analog that can inhibit viral RNA polymerase
What is the MOA of nirmatrelvir?
inhibitor of SARS-CoV-2 3C-like protease – 3CLpro cleaves polyprotein 1a and 1ab of SARS-CoV-2; peptidomimetic inhibits active site cysteine residue in 3CLpro and can no longer make active nonstructural proteins from polyprotein’ given with ritonavir to prevent inactivation of drug by CYP3A4
What is the MOA of molnupiravir?
polymerase inhibitor and chain terminator
o Prodrug/metabolism: prodrug of synthetic nucleoside derivative N4-hydroxycytidine and serves as polymerase inhibitor and chain terminator
o Side effects: mutagenic potential
