antiviral agents

• replicative cycles of herpes simplex virus, a DNA virus, and the probable sites of action of antiviral agents

  • viral replication is a regulated multistep process
  • after infection, a small number of immediate-early genes are transcribed
  • these genes encode proteins that regulate their own synthesis and are responsible for synthesis of early genes involved in genome replication
  • after DNA replication, the bulk of the herpesvirus genes (called late genes) are expressed into proteins that either incorporate into or aid in the assembly of progeny virions
• viral DNA polymerase inhibitors

  • deoxynucleoside analogues:
  • aciclovir
  • ganciclovir
  • valaciclovir
  • valganciclovir
  • deoxynucleotide analogues: cidofovir (CDV) (vistide)
• MOA of the prototype viral DNA polymerase inhibitor acyclovir

  • acyclovir is converted to the monophosphate (MP) derivative by a viral (eg herpes virus) thymidine kinase
  • acyclovir-MP is then phosphorylated to acyclovir-DP and acyclovir-TP by cellular kinases
  • acyclovir-TP competitively inhibit the binding of d-GTP to DNA polymerase
  • incorporation of an acyclovir-MP unit (from acyclovir-TP) into DNA leads to DNA chain termination and formation of inactive complex w/ the viral DNA polymerase
• selective toxicity of acyclovir

  • the viral enzymes for DNA synthesis are not as meticulous as the human counterparts and thus are easier to be "cheated" by the nucleoside analogs
  • faster (200x) phosphorylation of acyclovir by viral kinases
  • tighter binding of viral DNA polymerase to acyclovir-TP
  • incorporation of acyclovir into viral DNA, which terminates DNA elongation
• selective toxicity of acyclovir (cont.)

  • the genes of the virus-infected cells are altered to enhance the effect of the nucleoside analogs
  • faster uptake of acyclovir by nucleoside transporters on herpes virus-infected cells
  • more (40 - 100x) guanosine monophosphate kinase infected cells
• mechanism of resistance of acyclovir and other DNA polymerase inhibitors

  • point mutation: the viral genes are even more prone to mutation than the bacteria genes, leading to drug resistance
• valaciclovir, ganciclovir, and valganciclovir

  • valaciclovir
  • valine-derived
  • esterified version of acyclovir
  • greater oral bioavailability (~ 55%) than acyclovir
  • hydrolyzed by esterases to aciclovir and valine via hepatic first-pass metabolism
  • ganciclovir
  • very similar MOA compared to aciclovir
  • distribution, cell penetration, phosphorylation, and inhibition of viral DNA polymerase by delayed termination of DNA elongation
  • valganciclovir
  • similar to valaciclovir
  • valine-derived
  • esterified version of ganciclovir

  
• cidofovir (CDV) (vistide)

  • MOA:
  • this drug enters infected cells through human organic anion transporter
  • is converted to its diphosphate form by host cell kinases
  • this is equivalent to a triphosphate nucleotide
  • CDV-DP inhibits viral DNA polymerase (competes w/ dCTP) and acts as a DNA chain terminator
  • approved as an injectable for CMV retinitis in AIDS pts
  • also active against HSV infections, including those w/ resistance against acyclovir
  • also approved for several other viral infections
• cidofovir (CDV) (vistide) (cont.)

  • the drug is give IV, a topical (cream) form of the drug is also marketed
  • selective toxicity against virus:
  • CDV has been shown to have a selectivity of 8 to 600 fold for the viral DNA polymerases over the mammalian counter part
  • resistance:
  • mutations in the viral DNA polymerase that lead to decreased binding of the drug
• recommended treatment of COVID19

  • RNA dependent RNA polymerase inhibitors (RdRpl):
  • remdesivir
  • molnupiravir
  • IL-6 inhibitors:
  • siltuximab
  • sarilumab
  • toxilizumab
  • janus kinase (JK, JAK) inhibitors:
  • baricitinib (olumiant)
  • tofacitinib (xeljanz)
• MOA of remedesivir

  • a prodrug that is more lipophilic than a nucleoside, allowing it to diffuse quickly into infected cells
  • it is then metabolized into the nucleoside monophosphate form following a sequence of hydrolyses and molecular rearrangement
  • the nucleoside monophosphate analog then hijacks the endogenous phosphorylation pathway to yield the active nucleoside triphosphate analogue of ATP that is utilized by the viral RNA-dependent RNA polymerase (RdRp)
  • utilization of the nucleoside triphosphate analogue by RdRp induces delayed chain termination, which inhibits viral replication
• MOA of molnupiravir

  • rapidly hydrolyzed in the plasma to EIDD-1931
  • EIDD-1931 distributes into various tissues, enters cells through nucleoside transporter and is converted by host kinases into EIDD-1931 5'-triphosphate
  • EIDD-1931 5'-triphosphate mimics both CTP and UTP in two tautomer forms
  • EIDD-1931 5'-triphosphate is incorporated into viral mRNA by RdRp to cause extensive, lethal mutations
• IL-6 inhibitors for COVID-19 treatment

  • MOA:
  • interleukin (IL) -6 is a pleiotropic, pro-inflammation cytokine produced by a variety of cell types, including leukocytes and lung epithelial cells
  • COVID-19-associated systemic inflammation and hypoxemic respiratory failure can be associated w/ heightened IL-6 release
  • modulating IL-6 levels or the effects of IL-6 may reduce the duration and/or severity of COVID-19
  • two types of IL-6 inhibitors have been approved
  • anti-IL-6 mAbs (ie, siltuximab)
  • anti-IL-6 receptors mAbs (eg, sarilumab, toxilizumab)
• janus kinase (JK, JAK) inhibitors for COVID-19 treatment

  • MOA
  • janus kinase
  • a member of tyrosine kinase family
  • first discovered as "just another kinase" together w/ kinases that are invovled in oncology
  • later discovered to be an important player in inflammation
  • autophosphorylation of JK induces a conformational change
  • enables it to further phosphorylating and activating transcription factors called STATs (signal transducer and activator of transcription)
• janus kinase (JK, JAK) inhibitors for COVID-19 treatment (cont.)

  • MOA (cont.)
  • JK is a down stream effector of IL-6 and IL-6 receptor
  • similar to IL-6 inhibition: JK inhibition modulates inflammation caused by the 2 virus infection
  • two JK inhibitors have been approved
  • baricitinib (olumiant)
  • tofacitinib (xeljanz)