CATEGORIES, TYPES, INCREASES, AND DECREASES

Obligate intracellular parasite

What is the classification of viruses?

Dependent on host cell processes

What are viruses dependent on to replicate?

Block entry or exit, Be active inside the host cell

What must antiviral agents do to be effective?

Nonselective antivirals

What type of antivirals may interfere with host cell function and produce toxicities?

1950s

When were first-generation antivirals developed?

5-iododeoxyuridine and trifluorothymidine

What are two examples of first-generation antivirals?

Poor specificity

What characteristic defined first-generation antivirals regarding their target?

Inhibited host cell DNA together with viral DNA

What did first-generation antivirals inhibit due to their poor specificity?

Greater selectivity, Higher potency, in vivo stability, reduced toxicity

What are four focuses of recent research in developing newer antivirals?

Virustatic

How are antivirals functionally described (only working against replicating viruses)?

Do not affect latent viruses

What state of viruses are antivirals ineffective against?

Attachment

What is the first step in viral replication?

Entry

What is the second step in viral replication?

Uncoating

What is the third step in viral replication?

Synthesis of Early Regulatory Proteins

What is the fourth step in viral replication?

Nucleic Acid Synthesis (or Synthesis of RNA/DNA)

What is the fifth step in viral replication?

Synthesis of Structural Proteins

What is the sixth step in viral replication?

Assembly/Maturation of Viral Particles

What is the seventh step in viral replication?

Release

What is the eighth step in viral replication?

Enfuvirtide (HIV), maraviroc (HIV), docosanol (HSV), rimantadine, amantadine, palivizumab (ASV) (influenza)

Which drugs/agents block the Attachment and Entry phases of viral replication?

NATIs (HIV, HBV), NNATIs (HIV), acyclovir (HSV), foscarnet (CMV)

Which drugs/agents block the Nucleic Acid Synthesis phase (Step 5/Synthesis of RNA/DNA)?

Protease inhibitors (HIV)

Which drugs/agents block the Assembly/Maturation and Release phases (Steps 7/8)?

Amantadine and rimantadine

Which drugs block the Uncoating phase (Step 3) of viral replication?

interferon-alpha (HBV, HCV)

Which agent may block Early protein synthesis (Step 4)?

Fusion inhibitor

What class of drug is Enfuvirtide?

Protease inhibitors

What class of drug is Boceprevir?

Reverse transcriptase inhibitors

Which class of drugs includes Nucleosides, Nonnucleosides, and Integrase strand transfer inhibitors?

Large encapsulated virus, Double-stranded DNA

What are the structural characteristics of herpesvirus?

alpha-group (HSV-1, HSV-2, VZV)

Which group of herpesviruses infects epithelial cells and establishes latent infection in neurons?

Lymphotropic beta-group (CMV, HHV6 and HHV7)

Which group of herpesviruses causes acute and latent infection in various cell types?

gamma-group (EBV, KSHV/HHV8)

Which group of herpesviruses establishes latent infection in lymphoid cells?

Guanosine analog

What type of analog is Acyclovir?

3 phosphorylation steps

How many phosphorylation steps does Acyclovir require for activation?

Virus-specified thymidine kinase

Which enzyme converts Acyclovir to its monophosphate derivative?

Competition with deoxyGTP for viral DNA polymerase

What is one mechanism by which Acyclovir inhibits viral DNA synthesis?

Chain termination

What consequence follows the incorporation of Acyclovir into the viral DNA?

Alteration in the viral thymidine kinase or the DNA polymerase

What mechanisms can cause resistance to Acyclovir in HSV/VZV?

Foscarnet, cidofovir, trifluridine

Which three drugs have preserved activity against most prevalent acyclovir-resistant strains?

Reversible renal dysfunction (crystalline nephropathy) or neurologic toxicity (tremors, delirium, seizures)

What serious adverse effects are associated with Acyclovir IV infusion?

L-valyl ester of acyclovir

What is Valacyclovir chemically?

First-pass metabolism

How is Valacyclovir rapidly converted to Acyclovir after oral intake?

Serum levels = 3-5x greater than oral acyclovir

How do oral Valacyclovir serum levels compare to oral Acyclovir?

Diacetyl ester prodrug of 6-deoxypenciclovir (guanosine analog)

What is Famciclovir chemically?

Penciclovir

What active metabolite is Famciclovir rapidly converted to?

Competitive inhibition of viral DNA polymerase

What is the mechanism of action of Famciclovir/Penciclovir?

Does not cause chain termination

How does Famciclovir/Penciclovir inhibition differ from Acyclovir's mechanism?

Topical use (1% cream)

What is the primary route of administration and formulation for Penciclovir?

Saturated 22-C aliphatic alcohol

What is Docosanol chemically?

Inhibits fusion between the plasma membrane and the HSV envelope

What is the mechanism of action of Docosanol?

Fluorinated pyrimidine nucleoside

What is Trifluridine chemically?

Inhibits viral DNA synthesis, Incorporated into both viral and host DNA

What are the two main mechanisms of Trifluridine?

Helicase-primase inhibitors

What is the mechanism of action category for Pritelivir and Amenamevir (New Antivirals)?

beta-group herpesvirus

What type of herpesvirus is CMV?

Latently infects monocytes and bone marrow progenitors

What cell types does CMV latently infect?

Guanosine analog

What type of analog is Ganciclovir?

100x greater compared to acyclovir

How does Ganciclovir's activity against CMV compare to Acyclovir's?

Myelosuppression

What is a common and dose-limiting adverse effect of Ganciclovir, especially when combined with zidovudine, azathioprine or mycophenolate mofetil?

L-valyl ester prodrug of ganciclovir

What is Valganciclovir chemically?

Intestinal and hepatic esterases

Which enzymes rapidly hydrolyze Valganciclovir to Ganciclovir?

Inorganic pyrophosphate analog

What is Foscarnet (phosphonoformic acid) chemically?

DNA polymerase, RNA polymerase, and HIV reverse transcriptase

What three enzymes does Foscarnet directly inhibit?

Blocks the pyrophosphate binding site

What site does Foscarnet block on target enzymes?

Up to 30%

What percentage of Foscarnet is deposited in bone, having a half-life of several months?

Renal impairment

What is a major adverse effect of Foscarnet?

Pentamidine

Concomitant use of Foscarnet with which drug increases the risk of severe hypocalcemia?

Imipenem

Concomitant use of Foscarnet with which drug increases the risk of seizures?

Cytosine nucleotide analog

What is Cidofovir chemically?

Phosphorylation independent of viral enzymes

What unique characteristic defines Cidofovir's activation process?

Dose-dependent proximal tubular nephrotoxicity

What is the main adverse effect of Cidofovir?

High-dose probenecid

What must Cidofovir be administered with to block active tubular secretion and decrease nephrotoxicity?

CMV prophylaxis in CMV-seropositive recipients of allogenic hematopoietic stem cell transplants

What is Letermovir indicated for?

Inhibits CMV DNA terminase subunit pUL56

What is the mechanism of action of Letermovir?

Inhibits UL97 protein kinase and impairs viral DNA assembly

What is the mechanism of action of Maribavir?

Post-transplant CMV infection refractory to treatment with other anti-CMV agents

What is Maribavir indicated for?

Dysgeusia

What specific taste alteration is a side effect of Maribavir?

Eight helices of ssRNA, Lipid bilayer envelope

What is the Influenza virus composed of?

Hemagglutinin and neuraminidase

What two structures does the lipid bilayer envelope of Influenza contain?

Influenza A

Which type of influenza infects humans, pigs, horses, and birds?

Antigenic drift

What mechanism causes epidemics of Influenza A?

Antigenic shift

What mechanism causes pandemics of Influenza A?

Influenza B and C

Which types of influenza infect mostly children?

Neuraminidase inhibitors, analogs of sialic acid

What is the classification and chemical nature of Zanamivir and Oseltamivir?

Interferes with release of progeny influenza A and B from infected host cells

What is the mechanism of action of Neuraminidase inhibitors?

Early administration (within 48 hours of onset of illness)

What timing is crucial for Neuraminidase inhibitors to be effective?

Inhalation

What is the route of delivery for Zanamivir?

Cough, bronchospasm, reversible decrease in pulmonary function

What are three adverse effects of Zanamivir delivered via inhalation?

Orally

What is the route of delivery for Oseltamivir?

Nausea and vomiting

What are two adverse effects of Oseltamivir, which can be decreased by taking it with food?

Neuraminidase inhibitor (cyclopentane analog)

What is Peramivir chemically and functionally classified as?

Blocks M2 proton ion channel

What is the molecular mechanism of action of Amantadine and Rimantadine?

Inhibit uncoating of viral RNA

What phase of replication do Amantadine and Rimantadine inhibit?

Influenza A ONLY

Against which type of influenza are Amantadine and Rimantadine active?

Cap-dependent endonuclease inhibitor

What is the mechanism of action of Baloxavir?

Interferes with viral RNA transcription and blocks replication of Influenza A and B

What is the function of Baloxavir's mechanism of action?

Host cytokine; induction of intracellular signals; inhibits penetration, translation, transcription, protein processing, maturation and release

What is the description and mechanism of action of Interferons?

Guanosine analog; inhibit viral RNA-dependent polymerase

What is Ribavirin chemically and functionally classified as?

Monoclonal antibody

What type of agent is Palivizumab?

Immune response modifier

What is the mechanism of action of Imiquimod?

Orally bioavailable protease inhibitor active against MPRO

What is Nirmatrelvir?

Must be given with ritonavir to increase half-life and bioavailability (Ritonavir inhibits CYP3A4)

What is a critical administration requirement for Nirmatrelvir and why?