Antiviral Drugs for Respiratory Viral Infections PDF

13/10/2024 Antiviral Drugs for Respiratory Viral Infections A/Prof. Veysel Kayser, PhD [email protected] l The University of Sydney Page 1 1...

13/10/2024 Antiviral Drugs for Respiratory Viral Infections A/Prof. Veysel Kayser, PhD [email protected] l The University of Sydney Page 1 1 Pharmacy Learning Domains – Learning domain 2: Medicines: Drug Actions – Learning domain 3: Medicines: The Drug Substance The University of Sydney Assoc. Prof. Veysel Kayser © Page 2 2 1  13/10/2024 Learning Objectives – Virus life cycle – Where and how in the cycle antiviral agents work – Antiviral drugs used in treating influenza, RSV, COVID-19 The University of Sydney Assoc. Prof. Veysel Kayser © Page 3 3 Viruses The University of Sydney Assoc. Prof. Veysel Kayser © Page 4 4 2  13/10/2024 Viruses – 90 known virus families. This number grows by 2 each year1 – 5,000 of viruses are described in detail2 – Most viruses (~2,000) - MERS were discovered in 20th century3 – Size: 5 to 300 nm 1 Chapman, M. S. et al., Structural Folds of Viral Proteins. Advances in Protein Chemistry, 2003; Vol 64, p 125. The University of Sydney Assoc. Prof. Veysel Kayser © 2 Dimmock, N.J et al. (2007) Introduction to Modern Virology 6th edition, ISBN 1-4051-3645-6. Page 5 3 Norrby E., Nobel Prizes and the emerging virus concept. Arch. Virol. 2008;153(6):1109–23. 5 Influenza & RSV & SARS-CoV-2 The University of Sydney Assoc. Prof. Veysel Kayser © Page 6 6 3  13/10/2024 Typical Infectious Cycle (Influenza) – DNA viruses use the central dogma: DNA → RNA → protein – RNA viruses follow the central dogma in a different manner: RNA → RNA or RNA → protein 1. Attachment 2. Endocytosis 3. Fusion & uncoating 4. Transcription & replication 5. Assembly 6. Release The University of Sydney Assoc. Prof. Veysel Kayser © Nuwarda, R., Alharbi, A., Kayser, V. (2021). An overview of influenza viruses and vaccines. Vaccines, 9(9), 1032. Page 7 7 How do they work? – Antivirals can target viruses or pathways inside cells – Prevent infection of new cells – Some target viral proteins or cell mechanisms to stop viruses from entering cells – They block viral genome copying – Some mimic the bases that make up the viral genome, causing viruses to introduce errors when copying their genetic material – They can stop viral protein activation – Protease inhibitors stop production of new viruses by interfering with enzymes that make functional viral proteins Adapted from: https://cen.acs.org/content/dam/cen/100/4/WEB/10004-feature3new.pdf The University of Sydney Assoc. Prof. Veysel Kayser © Page 8 8 4  13/10/2024 Antivirals & Their Mechanisms of Action The University of Sydney Assoc. Prof. Veysel Kayser © Page 9 9 1. Attachment Antiviral Agents Affect 2. Endocytosis 3. Fusion & uncoating Inhibition of: 4. Transcription & replication – (or interference of) viral 5. Assembly attachment to host cell 6. Release – virus-associated enzymes – transcription process – translation process Interference with: – viral regulatory proteins – glycosylation, phosphorylation, sulfation etc. – assembly of viral proteins – release of virus from cell surface membrane The University of Sydney Assoc. Prof. Veysel Kayser © Page 10 Nuwarda, R., Alharbi, A., Kayser, V. (2021). An overview of influenza viruses and vaccines. Vaccines, 9(9), 1032. 10 5  13/10/2024 Antivirals for Respiratory Viral Infections Mechanism of Generic Name Trade Name Manufacturer Indications Target Virus Delivery Route Formulation & Ingredients Action Treatment & Prevention of Neuraminidase Oral (Capsules, Capsules: 75 mg; Oseltamivir Tamiflu Roche Influenza A & B Influenza inhibitor Suspension) Suspension: 12 mg/mL Treatment & Prevention of Neuraminidase Zanamivir Relenza GSK Influenza A & B Inhalation 5 mg per blister Influenza inhibitor Neuraminidase Peramivir Rapivab BioCryst Treatment of Severe Influenza Influenza A & B Intravenous 10 mg/mL injection inhibitor Baloxavir Cap-dependent Xofluza Roche Treatment of Influenza Influenza A & B Oral (Tablets) Tablets: 40 mg, 80 mg Marboxil endonuclease inhibitor RNA polymerase Remdesivir Veklury Gilead Sciences COVID-19 Treatment SARS-CoV-2 Intravenous 100 mg/20 mL concentrate inhibitor Nirmatrelvir + Nirmatrelvir 150 mg + Paxlovid Pfizer COVID-19 Treatment SARS-CoV-2 Protease inhibitor Oral (Tablets) Ritonavir Ritonavir 100 mg RNA polymerase Molnupiravir Lagevrio Merck COVID-19 Treatment SARS-CoV-2 Oral (Capsules) 200 mg/capsule inhibitor Treatment of RSV, Off-label RSV, Aerosolized, Aerosol: 20 mg/mL for 12– Ribavirin Virazole Bausch Health for Adenovirus & Adenovirus, Inhibits RNA synthesis Oral, IV 18 h/day Parainfluenza Parainfluenza Prevents viral entry Palivizumab Synagis AstraZeneca Prevention of RSV Prophylaxis RSV Intramuscular 15 mg/kg monthly injection by inhibiting fusion M2 ion channel Amantadine Symmetrel Endo Pharma Influenza A (historical) Influenza A blocker (inhibits Oral 100 mg tablets uncoating) Toyama SARS-CoV-2, RNA-dependent RNA Favipiravir Avigan The University of Sydney Assoc. Prof. Veysel Kayser © COVID-19 (select countries) Oral 200 mg tablets Page 11 Chemical Influenza polymerase inhibitor 11 Entry Inhibitor – Symmetrel (Amantadine) [Influenza A] Interacts with influenza viral M2 protein (ion channel) Blocks entry of protons into virion, prevents uncoating No longer used due to resistance Principles of Virology, ASM Press The University of Sydney Assoc. Prof. Veysel Kayser © Page 12 12 6  13/10/2024 Nucleoside/Nucleotide RNA-dependent RNA polymerase (RdRp) – These analogues mimic natural nucleosides/nucleotides and interfere with the viral replication machinery, particularly RNA-dependent RNA polymerases (RdRp) or other replication processes. Respiratory viruses like RSV, influenza, and coronaviruses use RdRp for replication. – This enzyme is different from reverse transcriptase, which makes NRTIs ineffective against respiratory viruses. – Treatments available are related to natural nucleosides. – Modifications include replacing the 3’ hydroxy group with hydrogen or azide. – Most are prodrugs – biologically inactive (or weakly active) compounds that become active only after metabolic activation (e.g., enzymatic conversion) in the body. This conversion improves absorption, distribution, or minimises toxicity, making prodrug antivirals effective for treating respiratory viral infections. – NOTE: Nucleosides consist of a base and sugar group; nucleotides consist of a base, sugar group, and at least one phosphate group. The University of Sydney Assoc. Prof. Veysel Kayser © Page 13 13 COVID-19 – Coronavirus - RNA virus – Member of SARS and MERS – Binds to ACE2 cell receptors via surface glycoprotein protein (spike protein) – Remdesevir: nucleoside analogue – Molnupiravir: inhibits RNA replication – Nirmatrelvir: protease inhibitor – Monoclonal antibodies (mAbs): block interactions between the binding of glycoproteins (spike protein) and ACE2 receptors which serve as prophylactics and therapeutics against COVID-19 – Vaccines: contain antigens to induce an immune response The University of Sydney Assoc. Prof. Veysel Kayser © Eroglu, B., Nuwarda, R., Ramzan, I., Kayser, V. (2022). A Narrative Review of CO VID-19 Vaccines. Vaccines, 10(1), 62 Page 14 Kayser, V., Ramzan, I. (2021). Vaccines and vaccination: history and emerging issues. Human Vaccines and Immunotherapeutics, 17(12), 5255-5268 14 7  13/10/2024 SARS-CoV-2 nucleoside analogues – Remdesivir [COVID-19] – It’s a chain terminator, a prodrug of adenosine nucleoside analogue – Developed for West African Ebolavirus outbreak in 2013 – Inhibits replication of multiple RNA viruses by mutagenesis – Found to inhibit SARS-CoV-2 replication in cells – Received EUA in US after phase 3 trials – Must be delivered intravenously – No effect on hospitalised COVID-19 patients – Difficult to synthesise (>30 reaction steps), expensive The University of Sydney Assoc. Prof. Veysel Kayser © Page 15 15 SARS-CoV-2 nucleoside analogues – Molnupiravir [COVID-19] – TGA approved orally active antiviral drug – Prodrug of cytidine nucleoside analogue – Templates as U – Inhibits replication of multiple RNA viruses in cell culture by mutagenesis – Found to inhibit SARS-CoV-2 replication in cells and in mice – Inhibits replication and transmission in ferrets – Phase 2a in humans: 0/47 culture negative at 5 days post symptom onset – Orally bioavailable The University of Sydney Assoc. Prof. Veysel Kayser © Page 16 16 8  13/10/2024 Nirmatrelvir (part of the combination drug Paxlovid) [COVID-19] – Nirmatrelvir/ritonavir combination sold under the brand name Paxlovid – Acts as an orally active covalent protease inhibitor, i.e., hinders processing of polyproteins – Utility of targeting the corona protease was first demonstrated in 2018 when previously treating lethal cat coronavirus disease – Ritonavir is also a protease inhibitor but also competes with cytochromes (CYPs) to reduce drug metabolism The University of Sydney Assoc. Prof. Veysel Kayser © Page 17 17 Influenza The University of Sydney Assoc. Prof. Veysel Kayser © Page 18 18 9  13/10/2024 Influenza Virus Nuwarda, R., Alharbi, A., Kayser, V. (2021). An overview of influenza viruses and vaccines. Vaccines, 9(9), 1032. The University of Sydney Assoc. Prof. Veysel Kayser © Page 19 19 Antivirals Against Influenza Virus Baloxavir Marboxil https://pubs.acs.org/doi/10.1021/acsinfecdis.7b00142 (2017) The University of Sydney Assoc. Prof. Veysel Kayser © Page 20 20 10  13/10/2024 Influenza virus NA inhibitors – Designed to mimic natural ligand, sialic acid – Closer inhibitor to natural compound, less likely target can change to avoid binding drug while maintaining viable function – NA catalytically cleaves glycosidic Sia bonds connected to a terminal sialic Gal Gal acid NA – Cleavage facilitates the virus exiting GlcNAc GlcNAc the host cell – Studies show that when virions are Core Sugar Core Sugar released, sialic acid is bound to the NA of the virion Protein Protein The University of Sydney Assoc. Prof. Veysel Kayser © Page 21 21 Neuraminidase (NA) inhibitors [Influenza] J Gen Virol. 1976 Oct;33(1):159-63. Principles of Virology, ASM Press The University of Sydney Assoc. Prof. Veysel Kayser © Page 22 22 11  13/10/2024 Neuraminidase Inhibitors – An Australian First in Design HO OH HO OH O H H (R) (R) H (R) (R) (E) HO O OH 1 (R) (R) HO O H (R) N (R) COOC2 H5 H H3C N (R) COOH H 2 (S) H3 C N (R) COOH (S) H3 C (S) (Z) 4 3 O H2 N O HO O HO Sialic acid DANA Oseltamivir (Tamiflu) HO OH H (R) (R) COOH HO O (R) (S) H N (R) COOH (S) H3 C HO (S) (Z) (R) NH (R) O HN HN NH2 (S) NHCOCH3 NH2 NH Peramivir Zanamivir (Relenza) The University of Sydney Assoc. Prof. Veysel Kayser © Page 23 23 Zanamivir (Relenza) – Inhaler [influenza] – Developed by replacing the 4-hydroxy HO OH group of DANA (R) H (R) – Binding to NA increases with 4-amino or 4- HO 1 6 (R) O guanidine groups H 2 – 4-Amino group binds to Glu 119 via a salt N (R) COOH H3 C 5 (S) bridge 4 (Z) – 4-guanidino group binds as a salt bridge to O HN NH2 Glu 119 and via a charge-charge interaction with Glu 227 – Inactive given orally NH The University of Sydney Assoc. Prof. Veysel Kayser © Page 24 24 12  13/10/2024 Oseltamivir phosphate (Tamiflu) – Capsule [influenza] – Prodrug Maximum binding occurs – X-ray crystallographic studies of NA with 3-pentyloxy side chain revealed an additional binding site – Hydrophobic region (Glu, Ala, Arg, Iso) – Binds C6 hydrophobic group O H – C5 acetamido carbonyl group binds to 6 Arg 152 H (R) (E) – C2 carboxyl binds to Arg 118, 292 N (R) COOC2 H5 H3C 5 2 (S) and 371 4 O H2 N The University of Sydney Assoc. Prof. Veysel Kayser © Page 25 25 Neuraminidase Inhibitor Resistance Testing Results on Samples Collected Since September 2019 – Circulating H1N1 and H3N2 viruses are largely resistant to Adamantanes, not recommended for use – Oseltamivir (Tamiflu) resistant strains of H1N1 and H3N2 exist – Substantial number of patients might become oseltamivir-resistant as a result of oseltamivir use – Zanamivir resistance has been rarely reported to date – More like sialic acid – Some reports of resistance in strains of avian flu H7N9 The University of Sydney Assoc. Prof. Veysel Kayser © Page 26 http://www.cdc.gov/flu/weekly/index.htm 26 13  13/10/2024 Baloxavir [Influenza] – Approved by FDA October 2018 for treatment of acute uncomplicated influenza in people 12 years of age and older who have been symptomatic for no more than 48 hours – Inhibitor of influenza endonuclease Principles of Virology, ASM Press The University of Sydney Assoc. Prof. Veysel Kayser © Page 27 27 Baloxavir marboxil is a selective inhibitor of influenza cap-dependent endonuclease – Prodrug – undergoes first pass metabolism to the active acid - baloxavir acid – Baloxavir acid inhibits cap-dependent endonuclease, and thereby the ‘cap-snatching’ step required by viral RNA in the initiation of viral genome transcription – Approved TGA 2020 O-demethylation The University of Sydney Assoc. Prof. Veysel Kayser © Page 28 28 14  13/10/2024 Broad-spectrum Antivirals The University of Sydney Assoc. Prof. Veysel Kayser © Page 29 29 Ribavirin [Respiratory Syncytial Virus (RSV)] RSV: – (-) sense, single-stranded RNA virus – Discovered in mid-50s from a chimpanzee – Common cause of hospitalisation w/ respiratory infections, e.g. bronchiolitis (infants), common colds (adults), pneumonia (elderly and immunocompromised) – Reinfection is common – RSV vaccines exist Ribavirin: – a nucleoside (guanosine) analog – a prodrug used for RSV, Hep C, some viral hemorrhagic fevers – was approved in 1986 – inhibits viral RNA synthesis (i.e. chain termination), viral mRNA capping, and lethal mutagenesis of RNA genome The University of Sydney Assoc. Prof. Veysel Kayser © Page 30 30 15  13/10/2024 Favipiravir (Avigan) – Broad-spectrum inhibitor of RNA viruses – Target: RdRp, a nucleoside analog – (+) RNA: picornaviruses (e.g., rhinoviruses – common cold), SARS-CoV-2 – (-) RNA: Respiratory syncytial virus, influenza virus (Orthomyxoviridae family) parainfluenza virus (Paramyxoviridae family) – Licensed in Japan to treat influenza & used in India for COVID-19 https://doi.org/10.1016/j.antiviral.2018.03.003 The University of Sydney Assoc. Prof. Veysel Kayser © Page 31 31 Feedback Questions HN N N N N NH2 HO O (S) (R) (Z) – What class of compounds are these drug? – Which compound is a nucleoside and which is a nucleotide analogue? How can you differentiate them? – What important process is required to render the compounds active? – Explain the life cycle for influenza A? – What drugs are approved for influenza A and how do they work? – Find an antiviral drug or drug combination that was recently (last 2 years) approved by the FDA/TGA and explain the mechanism of action. The University of Sydney Assoc. Prof. Veysel Kayser © Page 32 32 16  13/10/2024 Summary – Know classes of drugs and approved treatments – Know targets where drugs act within the viral life cycle – Know the binding site and structural features for the flu drugs – Know how and where drugs work for influenza, RSV, and COVID-19 – Know difference between nucleotide and nucleoside RdRp – READ: Erik De Clercq, and Guangdi Li Clin. Microbiol. Rev. 2016; doi:10.1128/CMR.00102-15 (Access via USYD Library) The University of Sydney Assoc. Prof. Veysel Kayser © Page 33 33 17