Pharma - Antivirals I (OA) PDF

Antiviral agents I Dr. Omamah Alfarisi November 2022 Case 1: A 27-year-old man has met a woman and they became intimately involved. After 2 months, the man started to get painful itchy sores on the genitalia. With fever and headache. Aft...

Antiviral agents I Dr. Omamah Alfarisi November 2022 Case 1: A 27-year-old man has met a woman and they became intimately involved. After 2 months, the man started to get painful itchy sores on the genitalia. With fever and headache. After being tested, he was positive for Herpes-simplex-virus2 (HSV2). This was the first time he acquired this infection  Anti-herpes(HSV) medications: what are the main viruses that are covered by these drugs? Are these viruses DNA or RNA viruses? Other related viruses are VZV, CMV, EBV What are the main categories of drugs that target HSV viruses?  Mechanism of action of anti-HSV Most of these drugs inhibit DNA polymerase by: Acyclo NRTS Competing with nucleotides on the DNA polymerase substrate site: a Nucleoside analogues so Yeti Acyclovir, valacyclovir, penciclovir, famciclovir, ganciclovir, valganciclovir, cidofovir, trifluridine famci These drugs need to be Activated by phosphorylation, analogues of ganci deoxyribonucleosidetriphosphates (dGTP) Require viral enzymes to phosphorylate and activate the drug: thus, inhibition of viral DNA synthesis rather than the host cell (selectivity) valgnci uridine NNRTs Inhibition of DNA polymerase: Non-nucleoside DNA polymerase inhibitors Foscarnet Mechanism of action Active drug/(Pro-drug): Acyclovir/(Valacyclovir) ~ found in HSV and VZV Penciclovir/(Famciclovir) Ganciclovir/(Valganciclovir) Mechanism of action of nucleoside analogues: Acyclovir ▪ They all require 3-steps of phosphorylation before being active: Viral kinase ▪ One phosphorylation step by viral kinase (e.g: thymidine kinase or UL-97 P kinase), ▪ then 2 phosphorylation steps by host cell kinases to nucleotide (guanosine) Acyclovir analogues Host kinase ▪ These analogues inhibit the viral DNA-polymerase ▪ Only actively replicating viruses are inhibited P P ▪ Resistance to thymidine kinase or DNA polymerase to one of the drugs can Acyclovir confer cross-resistance to other drugs Host kinase P P P Acyclovir Guanine analogue  Illustration by David H. Spach, MD What are you going to recommend to him for his HSV infection?  Acyclovir. Acyclovir and valacyclovir: Requires 3 phosphorylation steps for activation, first of which is by the viral thymidine kinase and then the di- & tri-phosphate by the host kinases Thus, acyclovir is selectively activated, and the active metabolite accumulates only in the infected cells Acyclovir is Active against: HSV2 (0.03–2.2 μg/mL), a tenth as potent against VZV (0.8–4.0 μg/mL) and EBV, least active against CMV (generally > 20 μg/mL) and HH-V6 Valacyclovir is a prodrug rapidly converted to acyclovir after oral administration via first- pass enzymatic hydrolysis in the liver and intestine. As effective as oral acyclovir in HSV and more effective in herpes zoster Adverse effects: depend on the route Local irritation - topical Nausea, vomiting, diarrhea, headache - oral Transient renal dysfunction or neurologic toxicity - high oral dose or IV Neutropenia in neonates  Famciclovir and penciclovir: Famciclovir is inactive prodrug of the active drug penciclovir. Penciclovir is similar to acyclovir in its spectrum of activity and potency against HSV and VZV. It is also inhibitory for HBV. Compared with acyclovir: Penciclovir is more efficiently phosphorylated by TK (higher intracellular concentration and for more prolonged period) but has lower affinity to viral DNA polymerase and thus has longer half-life and exposure in the infected cell. Valganciclovir and Ganciclovir: It is monophosphorylated intracellularly by viral TK during HSV infection and by a viral phosphotransferase encoded by the UL97 gene during CMV infection. Especially active against CMV About 100X more active than acyclovir against CMV and achieves 10X higher intracellular concentration- allowing for reducing dose frequency Valganciclovir is a prodrug of ganciclovir Resistance: Mutation in UL97 –kinase phosphotransferase- (more common) Mutation in UL54 –DNA polymerase- (high resistance, cross resistance with cidofovir and foscarnet) Adverse effects: Myelosuppression (with IV) Nausea, diarrhea, fever, rash, headache, peripheral neuropathy CNS toxicity (confusion, seizure, psychiatric disturbance) 2. Non-nucleoside DNA polymerase inhibitors: - Foscarnet- Does not require phosphorylation by viral or host kinases for activation Foscarnet inhibits viral nucleic acid synthesis by interacting directly, at the pyrophosphate site of the herpesvirus DNA polymerase or HIV reverse transcriptase. Foscarnet has ~100fold greater inhibitory effects against herpesvirus DNA polymerases than against host cellular DNA polymerase. (Selectivity) Herpesviruses resistant to foscarnet: mutations in the viral DNA polymerase. Intravenous foscarnet is effective for treatment of CMV retinitis, including ganciclovir- resistant infections, other types of CMV infection, and acyclovir-resistant HSV and VZV infections. Adverse effect: Nephrotoxicity (25%) – metabolic abnormalities (decrease Ca, Phosphate, Mg, K) – CNS toxicity Anti-influenza virus Influenza virus types: A, B, C A is the most common and most pathogenic Virus through its Hemagglutinin attaches to host cell’s sialic-acid receptors The influenza virions is then internalized in endosome where the viral M2 proton channel leads to uncoating of the virus The virus genetic material is released, replicated, and the virus is assembled At the end: viral budding: Virus is cleaved by the sialidase activity of NA proteins. The virion is then released from the cell. Virus Drug class Example Influenza A virus M2 inhibitor Amantadine Influenza A & B virus Neuraminidase inhibitor Oseltamivir  Amantadine Mechanism of action: primarily block the M2 proton channel in influenza A leading to: ▪ Early-stage inhibition effect: primarily inhibit the viral M2 proton channel while in the host cell endosome leading to prevention of viral uncoating at early stage ▪ Late-stage inhibition effect: prevention of M2 proton channel also lead to deformation in the HA protein and inhibition of proper viral assembly. ▪ M2 is only in influenza A, thus amantadine is not active against influenza B ▪ useful for the prevention and treatment of infections caused by influenza A virus Side effects: CNS-related side effects (dose-related). The CNS toxic effect can be increased with concomitant administration of antihistamine and anticholinergic drugs. Oseltamivir: Mechanism of action: neuraminidase inhibitor Viral Hemagglutinin is bound to host cell sialic acid on host-cell receptor Virus need to be released by cleaving this bond by viral neuraminidase Inhibition of this neuraminidase lead to inhibition of the viral release The neuraminidase inhibitors are active against many NA in both influenza A and B: Used for treatment of both Influenza A & B. Resistance is less compared to amantadine Side effects: are less toxic than amantadine. GI disturbances (resolve within 1-2days) Anti-hepatitis drugs Hepatitis viruses identified are (A, B, ,C, D). B and C are the most common pathogenic viruses. Hepatitis B virus HBV is a DNA double-stranded virus hepatitis C (HCV) is a single RNA virus  Nucleotide/nucleoside analogues ▪ They require phosphorylation to di- or tri- phosphate for activation. ▪ Some can competitively inhibit: ▪ HBV-related DNA polymerase ▪ Or inhibit HCV-related RNA-dependent-RNA polymerase. ▪ Ribavirin: exerts several mechanism of actions: 1. Monophosphated-ribavirin: inhibit viral GTP synthesis 2. Triphosphate ribavirin: directly inhibits viral mRNA polymerase by acting as nucleotide analogue. 3. It also inhibit the processing of the synthesized mRNA Drug Some side effects Adefovir Nephrotoxicity, hepatomegaly Entecavir Headache, dizziness, fatigue Ribavirin Hemolytic anaemia, teratogenicity Tenofovir Nephrotoxicity, bone loss Interferons Interferons are potent cytokines that possess antiviral, immunomodulatory, and antiproliferative activities. Three major classes of human IFNs: α, β, and γ. Mechanism of action: How does interferon work as antiviral? ❑ The binding of interferon to cell surface receptor molecules signals the cell to produce a series of antiviral proteins leading to several antiviral effects: ❑ Most of these interferons act to inhibit the translation of viral proteins by producing enzymes (methylase and ribonuclease) that degrade the viral mRNA. ❑ INF-a also activate macrophages and other neutrophils and cytotoxic T-lymphocytes to attack the virus. Attachment of IFN proteins to large inert polyethylene glycol (PEG) molecules (pegylation): slows absorption, decreases clearance, and provides higher and more prolonged serum concentrations that enable once weekly dosing. Adverse effects: GI irritation, flu-like symptoms, neutropenia, profound fatigue, alopecia, thyroid dysfunction. Simeprevir: Inhibits the non-structural3/4A protease The NS3/4A protease: essential for generating mature viral proteins required for viral replication, suppress the host antiviral immune system. Adverse effects: anaemia, pruritus, transient increase bilirubin