Lecture 21 Antiviral Therapy PDF

Objectives 1. Identify the potential drug targets in viral infections 2. List antiviral agents for human viral infections (HIV, HSV, respiratory viral infections, hepatic viral infections) 3. For each of these drugs: a. Explain its mechanism of action b. Describe clinically-relevant pharmac...

Objectives 1. Identify the potential drug targets in viral infections 2. List antiviral agents for human viral infections (HIV, HSV, respiratory viral infections, hepatic viral infections) 3. For each of these drugs: a. Explain its mechanism of action b. Describe clinically-relevant pharmacokinetics c. Identify major adverse effects  Principles of Antiviral Therapy Dr. Raya Al Maskari Sultan Qaboos University © College of Medicine and Health Sciences  Objectives 1. Identify the potential drug targets in viral infections 2. List antiviral agents for human viral infections (HIV, HSV, respiratory viral infections, hepatic viral infections) 3. For each of these drugs: a. Explain its mechanism of action b. Describe clinically-relevant pharmacokinetics c. Identify major adverse effects The Challenge Viruses (unlike bacteria) are not cells Lack cell walls Lack cell membranes Lack their own metabolic machinery Utilize metabolic processes of the host Clinical symptoms appear late when most of the viral particles have replicated Rise of the Antivirals  Points of Attack Block viral binding or entry Interfere with the production of proteins required to form new viruses Prevent viruses from making new RNA copies  Antiretroviral Therapy HIV Infection Saves lives Prolongs life-expectancy Reduces chance of transmission  Antiretroviral Therapy Classification Nucleoside and nucleotide reverse Chemokine transcriptase receptor inhibitors (NRTIs) antagonist Non-nucleoside Protease Integrase reverse Inhibitors strand transcriptase transfer inhibitors (NNRTIs) inhibitor Non Nucleoside Reverse Transcriptase Inhibitors Chemically diverse compounds which bind the reverse transcriptase enzyme near the catalytic site  enzyme inhibition Efavirenz (oral)  Effect on CYP450 Enzymes Potent inhibitor of CYP2B6 What effect might this have on drugs cleared by CYP2B6? https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4075192/ Enzyme inhibition: decreased drug metabolism and increased potential for toxicity  Nucleoside and Nucleotide Reverse Transcriptase Inhibitors Prodrugs, activated after phosphorylation by host cells Nucleoside/nucleotide analogues which lack 3’-hydroxyl group act as false substrates  phosphorylated by host cell enzymes  incorporated into growing DNA chain  chain termination Prevent formation Affinity to host DNA polymerase < of 3’-5’ HIV phosphodiesteras e bond Zidovudine (nucleotide analogue) Tenofovir (nucleoside analogue) Adverse Effects Most toxicities occur due to inhibition of mitochondrial DNA polymerase in certain tissues  Protease Inhibitors (PI) Inhibit various viral proteases which are responsible for converting viral polyproteins into structural and functional proteins  prevent viral maturation  noninfectious virions Gag and Gag-pol PI: Atazanavir NS 3/A4 PI : Boceprevir NS 5A PI: Daclatasvir Significant CYP450 drug-drug interactions Clinical utility: HIV, Hep C Adverse Drug Reactions Fat redistribution with chronic use – accumulation in the abdomen and base of the neck + loss from the extremities Integrase Strand Transfer Inhibitors (INSTIs) Inhibit integrase  prevent insertion Raltegravir of viral DNA into the host genome HIV uses integrase to insert (integrate) its viral DNA into the DNA of the host CD4 cell. Examine the plot – observe what happens when raltegravir is given with Plasma Concentration an antacid (dashed lines) Reduced bioavailability due to chelation Entry Inhibitor/CCR5 Antagonist Blocks the chemokine coreceptor CCR5 which facilitates HIV entry through the membrane into the cell Maraviroc Effective only in patients with the R5 strain Fusion Inhibitor Blocks the conformational change of the viral transmembrane glycoprotein gp41 when HIV binds to the host cell surface Enfuvirtide (subcutaneous)  Treatment of Herpes Virus Infections Cold sores Viral encephalitis Genital infections DNA Polymerase Inhibitors Guanosine analogue  monophosphorylated by the viral thymidine kinase  converted to triphosphate form by the host cell kinases  competes with dGTP and gets incorporated into the viral DNA  premature DNA chain termination Acyclovir (oral, IV, topical)  Treatment of Respiratory Viral Infections Influenza A and B Respiratory syncytial virus SARS-CoV-2, COVID-19  Neuraminidase Inhibitors Inhibit viral neuraminidase enzyme  prevent release of new Oseltamivir virions  prevent viral spread (prodrug) Endonucleotide Inhibitors Inhibit endonuclease activity in the influenza viral RNA polymerase  prevents viral gene transcription and viral replication Baloxavir Ribavirin Synthetic guanosine analog  inhibits RNA and DNA replication Broad spectrum of activity against RNA and DNA viruses (RSV, Hep C)  Treatment of Hepatic Viral Infections Hepatitis B Hepatitis C Treatment of Hepatitis B Interferons: Naturally occurring glycoproteins, synthesized using recombinant DNA technology  induce host enzymes  degrade viral mRNA and tRNA “Pegylated” formulations: larger molecules = longer duration of action Therapeutic Strategy: Interferons NRTIs Hepatitis C Treatment All-oral treatments: Improved response highly effective, Strategy: Historical but suboptimal – simple, well-tolerated Perspective early DAAs genotype specific Risk of liver Direct-Acting All-Oral Antivirals Therapy 100 decompensation in (DAAs) 2013 Current 95+ cirrhotic patients Peginterferon 2011 90+ (pegIFN) 80 Ribavirin 2001 (RBV) 70+ Standard Interferon 1998 60 (IFN) 55 1991 42 39 40 34 20 16 6 0 IFN IFN IFN/RBV IFN/RBV PegIFN PegIFN/RBV PegIFN/ DAA + All–Oral 6 Mos 12 Mos 6 Mos 12 Mos 12 Mos 12 Mos RBV + RBV ± DAA± DAA PegIFN RBV Box T, Clinical Care Options. 2017  Direct Acting Antivirals Target different parts of the HCV polyprotein  prevent HCV replication and assembly NS3/NS4A inhibitors NS5A inhibitors NS5B inhibitors Glecaprevir Ledipasvir Sofosbuvir Significant CYP450 drug-drug interactions Direct Acting Antivirals – Treatment Options  Q&A Sultan Qaboos University © College of Medicine and Health Sciences  Efavirenz (oral) Skin rash Non nucleoside reverse transcriptase inhibitors (NNRTIs) GI disturbance Vivid dreams Potent inhibitor of CYP2B6 Prodrugs Hepato-steatosis (fatty liver) Nucleoside and Nucleotide reverse transcriptase Zidovudine (nucleotide analogue) inhibitors (NRTIs) Inhibition of mitochondrial DNA Lactic acidosis polymerase Tenofovir (nucleoside analogue) Lipodystrophy HIV infection Gag & Gag-pol PI Atazanavir Protease inhibitors (PI) NS 3/A4 PI Boceprevir HIV & Hep C Buffalo hump: Fat redistribution with chronic use NS 5A PI Daclatasvir Integrase strand transfer inhibitors (INSTIs) Raltegravir Entry inhibitors/ CCR5 antagonist Maraviroc Fusion inhibitors Enfuvirtide (subcutaneous) Cold sores Viral encephalitis Herpes virus infections Genital infections DNA polymerase inhibitors Acyclovir (oral, IV, topical) Antiviral drugs Hepatitis B Hepatitis C Hepatic viral infections Therapeutic strategy: Interferons & NRTIs NS3/ NS4A inhibitors Glecaprevir NS5A inhibitors Ledipasvir Direct acting antivirals NS5B inhibitors Sofosbuvir Sofosbuvir + Velpatasvir Optimum pangenotypic regimens Pibrentasvir + Glecaprevir Influenza A & B Respiratory syncytial virus Respiratory viral infections SARS-CoV-2, COVID-19 Neuraminidase inhibitors Oseltamivir (prodrug) GI disturbance Endonucleotide inhibitors Baloxavir Diarrhoea u