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Applied Biomedical Sciences in Microbiology Lecture 7: Viral Antimicrobials Instructor: Ositadinma B. Akaeme Classification: P2 SUMMER 2016 Viral Antimicrobials Instructor: Ositadinma B. Akaeme July Objectives • Be able to identify the different classifications of antiviral agents • Understand the MOA of the tricyclic amine Amantadine and know that Rimantadine has a longer half-life • Understand the MOA of guanosine analogs • Understand the MOA and MOR of the nucleoside analog acyclovir and its clinical uses • Understand the MOA of glycoproteins • Understand the MOA of pyrophosphate derivatives • Know the clinical uses of nucleoside reverse transcriptase inhibitors • Understand the MOA and MOR and non-nucleoside reverse transcriptase inhibitors • Understand the MOA of protease inhibitors • Know the classes of antiviral drugs that interfere with viral uncoating, nucleic acid synthesis, and assembly and release of viral products • Understand the difference between PrEP and PEP Classification of Antiviral Agents Tricyclic Amines Guanosine Analogs Glycoproteins Nucleoside Analogs Nucleoside RTIs NNRTIs Pyrophosphanate derivative Protease Inhibitors Tricyclic amines Major Sites of Drug Action on viral replication d. Tricyclic Amines • Amantadine • MOA • Blocks viral RNA uncoating of influenza A, inhibiting viral replication • Causes dopamine release in CNS • Clinical Uses • Prophylaxis for influenza A • Influenza treatment • Initial therapy for Parkinson’s disease (due to DA release triggered in CNS) • Rimantadine • MOA • Blocks viral uncoating • Longer half-life than amantadine • Clinical Uses • Influenza treatment Guanosine analogs Guanosine Analogs • Ribavirin • MOA • Inhibits synthesis of GTP • Inhibits viral RNA-dependent RNA polymerase • Inhibits capping of viral mRNA • Clinical Uses • • • • • Aerosolized form for influenza treatment Aerosolized treatment of bronchiolitis caused by RSV Keratitis due to herpes IV treatment decreases mortality if used early in Lassa fever Treatment of hepatitis C (with interferon) Glycoproteins Glycoproteins • Interferon alpha and Interferon beta • MOA • Endogenous proteins with multiple mechanisms of action that exert antiviral, immunoregulatory and antiproliferative activities • Clinical Uses • • • • • • • Chronic hepatitis C Chronic myelogenous leukemia Malignant myeloma Hairy cell leukemia AIDS related Kaposis sarcoma Genital warts Relapsing multiple sclerosis Pyrophosphate derivatives Pyrophosphate Derivatives • Foscarnet • MOA • Directly inhibits viral RNA and DNA polymerases and HIV reverse transcriptase by interacting with the pyrophosphate binding site • MOR • Via point mutations in the DNA polymerase gene • Clinical Uses • CMV retinitis, colitis, and esophagitis • Acyclovir-resistant HSV infection • Acyclovir-resistant VZV infection Nucleoside analogs Nucleoside Analogs • Acyclovir • MOA • First phosphorylation by viral thymidine kinase • Second and third phosphorylations by host cell kinases • Acyclovir-triphosphate is then incorporated into viral DNA causing premature termination • MOR • Via alteration in viral thymidine kinase • Via alteration in DNA polymerase • Confers cross resistance to valacyclovir, famciclovir, and ganciclovir • Clinical Uses • Primary or recurrent genital herpes • HSV encephalitis or neonatal HSV infection • HSV lesions d. c. Nucleoside Analogs • Valacyclovir • MOA • First phosphorylation by viral thymidine kinase • Second and third phosphorylations by host cell kinases • Acyclovir-triphosphate is then incorporated into viral DNA causing premature termination • Clinical Uses • Primary or recurrent genital herpes as well as prophylaxis • Herpes zoster infection • Prevention of CMV following organ transplantation Nucleoside Analogs • Ganciclovir • MOA • First phosphorylation by viral thymidine kinase • Triphosphorylated form inhibits DNA polymerases of CMV and HSV • MOR • • • • Via alteration in viral kinase Clinical Uses CMV retinitis, colitis, or esophagitis in HIV patients CMV prophylaxis in HIV patients Nucleoside Analogs • Trifluridine • MOA • Phosphorylated by cellular enzymes • Active form inhibits viral DNA synthesis • Clinical Uses • Drug of choice for keratoconjunctivitis due to HSV-1 or HSV-2 • Acyclovir resistant HSV infections Nucleoside Analogs • Vidarabine • MOA • Phosphorylated by intracellular enzymes • Activated form inhibits viral DNA polymerase • Clinical Uses • Keratitis due to herpes Nucleoside reverse transcriptase inhibitors NRTI Reverse transcriptase: an RNA-dependent DNA polymerase e. f. Nucleoside reverse transcriptase inhibitors • Zidovudine/AZT/ZDV • MOA • • • • Phosphorylated to form a nucleotide analog by cellular kinases Inhibits reverse transcriptase of HIV-1 and HIV-2 Causes chain termination Reverse transcriptase is more susceptible to inhibitory effect of these than mammalian DNA polymerase • MOR • Develops rapidly with monotherapy • Clinical Uses • • • • HIV treatment Often used with lamivudine (3TC) Reduces vertical transmission to fetus Palliative treatment (only can eliminate active virus) Nucleoside reverse transcriptase inhibitors • Didanosine/ddI • MOA • Activated by cellular kinases • Phosphorylated form inhibits reverse transcriptase and causes chain termination • MOR • Confers cross resistance to abacavir, ddc (Zalcitabine) and 3TC (Lamivudine) • Clinical Uses • HIV treatment • Often used with d4T (Stavudine) Nucleoside reverse transcriptase inhibitors • Zalcitabine/ddC • MOA • Inhibits reverse transcriptase • Clinical Uses • HIV treatment • Used in combination therapy to avoid drug resistance Nucleoside reverse transcriptase inhibitors • Lamivudine/3TC • MOA • Phosphorylated by host cell kinases • Inhibits reverse transcriptase • MOR • Confers cross resistance to abacavir, ddI, and ddC • Clinical Uses • HIV treatment • Chronic hepatitis B treatment Nucleoside reverse transcriptase inhibitors • Stavudine/d4T • MOA • Inhibits reverse transcriptase • MOR • Confers cross resistance to ddI and ddC • Clinical Uses • HIV treatment • Convenient for use in HIV patients because it can be taken without regard to meals only twice daily • Used with ddI or 3TC Nucleoside reverse transcriptase inhibitors • Abacavir • MOA • Active metabolite is incorporated into viral DNA where it prevents viral DNA elongation and inhibits the activity of HIV reverse transcriptase • MOR • Confers resistance to 3TC, ddI, and ddC • Clinical Uses • HIV treatment a. Non-nucleoside reverse transcriptase inhibitors NNRTIs Non-Nucleoside reverse transcriptase inhibitors • Drugs: • Nevirapine, Delavirdine, and Efavirenz • MOA • Inhibit reverse transcriptase • MOR • Via mutations in the pol gene, which encodes for reverse transcriptase • Clinical Uses • HIV treatment • Can be combined with NRTIs for HIV treatment • Allows protease inhibitors to be saved for later treatment Protease inhibitors Protease inhibitors • Drugs: • Indinavir, Saquinavir, Ritonavir, Amprenavir • MOA • Inhibit viral protease that cleaves precursor proteins • MOR • Via mutations in the pol gene, which encodes for reverse transcriptase • Confers cross resistance to class members • Clinical Uses • HIV treatment • Can be used alone (resistance will develop) • Usually used in combination with nucleoside analogue b. Pre-exposure prophylaxis PrEP PrEP • PrEP is a pill taken to prevent HIV infection from taking hold in the event of exposure to the virus • Option for high risk populations • Can reduce chance of infection up to 92% • Taken once daily • Oral Tenofovir disoproxil fumarate TDF • Reverse transcriptase inhibitor • Oral TDF+ emtricitabine TDF-FTC • Approved for use under the name Truvada by the FDA in 2012 • What are some of the ethical implications of offering such a drug? g. Post-exposure prophylaxis PEP PEP • The use of antiretroviral medicines as soon as possible • Begin prophylaxis NO MORE than 72 hours (3 days) after confirmed or possible exposure • Prevents HIV from copying itself and infecting other cells • 2-3 drugs usually prescribed • 28 day therapy • It is NOT a guarantee that PEP will work but it will greatly reduce chances of infection References • Lange Smart Charts Pharmacology Katherine Pelletier McGraw Hill, 2003 ISBN: 0-07-138878-8 ISSN: 1542-6866
