1-Lecture+1_ID2+MC+Lecture+1_Antivirals_non-retroviral+non-hep.pdf

Antivirals: Non-retroviral, Non-hepatitis Drugs (Influenza, COVID-19, RSV, HSV and CMV) Gregory D. Cuny Integrated Module – Infectious Diseases II November 6, 2023 2 Learning Objectives • Identify chemical and/or pharmacological classification of non-retroviral, non-hepatitis drugs. • Identify p...

Antivirals: Non-retroviral, Non-hepatitis Drugs (Influenza, COVID-19, RSV, HSV and CMV) Gregory D. Cuny Integrated Module – Infectious Diseases II November 6, 2023 2 Learning Objectives • Identify chemical and/or pharmacological classification of non-retroviral, non-hepatitis drugs. • Identify physicochemical and stability properties of nonretroviral, non-hepatitis drugs. • Discuss the ADME and illustrate the metabolic pathways to active and inactive metabolites of non-retroviral, nonhepatitis drugs. • Identify possible toxicities and drug-drug interactions of non-retroviral, non-hepatitis drugs. 3 Antiviral Drugs Antiviral Drugs Nonretroviral, Non-hepatitis Retroviral Hepatitis 4 Non-retroviral, Non-hepatitis Drug List Influenza • Oseltamivir (Tamiflu)** – Zanamivir – Peramivir • Baloxavir marboxil • Amantidine and rimantadine COVID-19 • Remdesivir • Molnupiravir • Nirmatrelvir Respiratory syncytial virus (RSV) • Ribavirin Herpesviruses • Acyclovir** • Valacyclovir (Valtrex)** • Penciclovir • Famciclovir • Valganciclovir (Valcyte)** • Ganciclovir • Cidofovir • Foscarnet • Letermovir 5 Drugs to Treat Influenza Neuraminidase (NA) Inhibitors 6 Drugs to Treat Influenza Neuraminidase Inhibitors – Structure Analysis 7 Drugs to Treat Influenza Neuraminidase Inhibitors – Transition State Mimetic Substrate E Transition State Design drug to mimic the TS Designed drug will inhibit the enzyme Product 8 Drugs to Treat Influenza Neuraminidase Inhibitors – Transition State Mimetic NA H2O Transition State 9 Drugs to Treat Influenza Neuraminidase Inhibitors – Transition State Mimetic Do you think the ester is the active drug? 10 Drugs to Treat Influenza Neuraminidase Inhibitors – Transition State Mimetic R371 D151 PDB:2QWK 11 Drugs to Treat Influenza ▪ Phosphate salt enhances aqueous solubility (~1.6 g/L). ▪ Readily absorbed from the GI tract following oral administration. ▪ The prodrug ester is hydrolyzed to the active carboxylic acid primarily in the liver. ▪ The active metabolite is not further metabolized and is eliminated in the urine. 12 Drugs to Treat Influenza Cap-dependent Endonuclease Inhibitor Baloxavir marboxil 13 Drugs to Treat Influenza Baloxavir marboxil - prodrug 14 Drugs to Treat Influenza Cap-dependent Endonuclease Baloxavir Acid Complex PDB:6SF8 Mn+2 Mn+2 15 Drugs to Treat Influenza ▪ Baloxavir marboxil is poorly soluble in water, but is orally bioavailable. ▪ The prodrug is almost completely hydrolyzed to the active baloxavir acid. ▪ Baloxavir’s main metabolite is the corresponding glucuronide. Mn+2 Mn+2 16 Drugs to Treat Influenza Baloxavir marboxil DDI Avoid co-administration with polyvalent cation-containing laxatives, antacids, or oral supplements (e.g., calcium, iron, magnesium, selenium, or zinc). Why? Mn +2 Mn+2 17 Drugs to Treat Influenza RNA virus entry inhibitors Amantidine and Rimantadine Mn+2 Mn+2 18 Drugs to Treat COVID-19 RNA-dependent RNA polymerase (RdRP) inhibitor Mn+2 Mn+2 19 Drugs to Treat COVID-19 Metabolism Mn+2 Mn+2 20 Drugs to Treat COVID-19 Mn+2 Mn+2 21 Drugs to Treat COVID-19 CryoEM structure of RdRP inhibitor complex Mn+2 Mn+2 RNA template Remdesivir active metabolite RdRP Mg+2 22 Drugs to Treat COVID-19 Mn+2 Mn+2 Yin, W. et al. Science 2020, 368, 1499-1504 23 Drugs to Treat COVID-19 ▪ Remdesivir is poorly soluble in water. Mn+2 Mn+2 ▪ Remdesivir is formulated with sulfobutylether-β-cyclodextrin sodium salt (SBECD) to increase aqueous solubility for intravenous infusion. 24 Drugs to Treat COVID-19 RNA-dependent RNA polymerase (RdRP) inhibitor substrate Mn+2 Mn+2 25 Drugs to Treat COVID-19 Mn+2 Mn+2 26 Drugs to Treat COVID-19 ▪ Molnupiravir is water soluble (2 g / L). ▪ Metabolized to uridine and/or cytidine via the endogenous pyrimidine metabolism pathways. Mn+2 Mn+2 27 Drugs to Treat COVID-19 Paxlovid = Nirmatrelvir + Mn+2 Ritonavir Mn+2 main protease CYP3A4 inhibitor (Mpro)* inhibitor as a PK enhancer * Formally known as 3C-like protease 28 Drugs to Treat COVID-19 Nirmatrelvir bound to main protease (Mpro) H163 H41 C145 E166 M49 P168 29 Drugs to Treat COVID-19 * * * ▪ Nirmatrelvir is a substrate for CYP3A4 (sites *). Mn+2 Mn+2 ▪ But when co-administered with ritonavir, nirmatrelvir is primarily eliminated by the kidneys. 30 Drug to Treat Respiratory Syncytial Virus (RSV) Nucleoside Inhibitor Mn+2 Mn+2 31 Drug to Treat Respiratory Syncytial Virus (RSV) ▪ Oral bioavailability is 45-50%. Prodrug Metabolism Mn+2 Mn+2 32 Drugs to Treat Herpesviruses DNA Polymerase Inhibitors O-linked Mn+2 C-linked Mn+2 Pro-drug 33 Drugs to Treat Herpesviruses Pro-drug Metabolism Mn+2 Mn+2 34 Drugs to Treat Herpesviruses Metabolism Mn+2 Penciclovir Mn+2 Penciclovir triphosphate (active metabolite) 35 Drugs to Treat Herpesviruses ▪ Valacyclovir is an HCl salt with increased water solubility compared to acyclovir (174 mg/mL vs < 3 mg/mL). Mn+2 ▪ Valacyclovir has greater GI absorption and greater oral bioavailability compared to acyclovir (54% vs 20%). 36 Drugs to Treat Herpesviruses DNA Polymerase Inhibitors Pro-drug Analog of cytosine Mn+2 Mn+2 37 Drugs to Treat Herpesviruses DNA Polymerase Inhibitors 38 Drugs to Treat Herpesviruses Pro-drug Metabolism 39 Drugs to Treat Herpesviruses ▪ Valganciclovir is an HCl salt with increased water solubility compared to ganciclovir (70 mg/mL vs 2.6 mg/mL). ▪ Valganciclovir is well absorbed from the gastrointestinal tract with an oral bioavailability of 60%. ▪ Valganciclovir is rapidly metabolized in the intestinal wall and liver to ganciclovir. ▪ Ganciclovir is primary excreted unchanged in urine.