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TREATMENT of VIRAL RESPIRATORY INFECTIONS Erik TREATMENT OF VIRAL RESPIRATORY INFECTIONS Erik DE CLERCQ Rega Institute for Medical Research, K.U.Leuven B-3000 Leuven, Belgium RESPIRATORY TRACT VIRUS INFECTIONS ADENOVIRIDAE : Adenoviruses HERPESVIRIDAE : Cytomegalovirus, Varicella-zoster virus PICORNAVIRIDAE : Enteroviruses (Coxsackie B, ECHO) Rhinoviruses CORONAVIRIDAE : Coronaviruses ORTHOMYXOVIRIDAE : Influenza (A, B, C) viruses PARAMYXOVIRIDAE : Parainfluenza viruses Respiratory syncytial virus “SARS (Severe Acute Respiratory Disease) virus” RESPIRATORY TRACT VIRAL DISEASES Adenoviruses: Adenoiditis, Pharyngitis, Bronchopneumonitis Cytomegalovirus: Interstitial pneumonitis Varicella-zoster virus: Pneumonitis Enteroviruses (Coxsackie B, ECHO): URTI (Upper Respiratory Tract Infections) Rhinoviruses: Common cold Coronaviruses: Common cold Influenza viruses: Influenza (upper and lower respiratory tract infections) Parainfluenza viruses: Parainfluenza (laryngitis, tracheitis) Respiratory syncytial virus: Bronchopneumonitis INFLUENZA VIRUS Influenza virus Electron micrographs of purified influenza virions. Hemagglutinin (HA ) and neuraminidase (NA) can be seen on the envelope of viral particles. Ribonucleoproteins (RNPs) are located inside the virions. http://www.virology.net/Big_Virology/BVRNAortho.html Influenza Layne et al., Science 293: 1729 (2001) NA (neuraminidase) Lipid bilayer M1 (membrane protein) M2 (ion channel) RNPs (RNA, NP) Transcriptase complex (PB1, PB2 and PA) HA (hemagglutinin) Simplified representation of the influenza virion showing the neuraminidase (NA) glycoprotein, the hemagglutinin (HA) glycoprotein and the matrix M2 protein M2 McClellan and Perry, Drugs 61: 263-283 (2001) Distribution of influenza A hemagglutinin (H) subtypes in nature Figure adapted from Murphy & Webster. Orthomyxoviruses. http://www.brown.edu/Courses/Bio_160/Projects1999/flu/mechanism.html Distribution of influenza A hemagglutinins in nature http://www.brown.edu/Courses/Bio_160/Projects1999/flu/mechanism.html Distribution of influenza A neuraminidases in nature http://www.brown.edu/Courses/Bio_160/Projects1999/flu/mechanism.html Amantadine/rimantadine: mechanism of action limited to influenza A viruses H NH .HCl H 2 H Amantadine Symmetrel® H NH2.HCl H CH3 H Rimantadine Flumadine® The tetrameric M2 helix bundle Sansom & Kerr, Protein Eng. 6: 65-74 (1993) Neuraminidase (NA): Cleaves sialic acid from cell-surface glycoprotein Glycoproteins and neuraminidase Sialic acid Sialic acid α2,3 ! Galactose Galactose β1,4 N-acetyl-glucosamine N-acetyl-glucosamine Core sugars Core sugars protein protein Influenza virus neuraminidase Functions: • removes terminal sialic acid residues • promotes release of virus particles from the cells • destroys cellular receptors recognized by hemagglutinin • prevents virus aggregation at the cell surface • prevents viral inactivation by respiratory mucus NEURAMINIDASE INHIBITORS GG167 GS4104, Ro64-0796 4-Guanidino-Neu5Ac2en Ethyl ester of GS4071 Zanamivir Oseltamivir Relenza® Tamiflu® HO OH H O HO O H N OH H3C OH O HO Sialic acid N-Acetylneuraminic acid (NANA) HO HO OH OH HO HO H O H δ+ O O O H H H3C N OH influenza H3C N OH O O δ- neuraminidase O R O HO R HO Sialyl α-glycoside Transition state R = glycoprotein Abdel-Magid et al., Curr. Opin. Drug Discov. Dev. 4: 776-791 (2001) HO HO OH OH HO HO H H O O Ο H O O H 2 H H C N H C N OH 3 3 ΟΟΗΗ ΟΟΗΗ O O HO HO R-O- R-OH Transition state Sialic acid Abdel-Magid et al., Curr. Opin. Drug Discov. Dev. 4: 776-791 (2001) HO OH HO H O Ο H H3C N ΟΟΗΗ O HO DANA Abdel-Magid et al., Curr. Opin. Drug Discov. Dev. 4: 776-791 (2001) HO OH HO H O Ο H F N ΟΟΗΗ F F O HO FANA Abdel-Magid et al., Curr. Opin. Drug Discov. Dev. 4: 776-791 (2001) HO OH HO H O Ο H H3C N ΟΟΗΗ O HN NH H2N Zanamivir Relenza® HO O P HO OH H3C O Ο H C 3 H N H3CO O NH2 CH3 Oseltamivir phosphate Tamiflu® Oseltamivir = GS4104 = oral prodrug (ethyl ester) form of GS4071 H3C O H CO 3 H N C H3C OH O NH2 GS4071 GS4071 bound to influenza neuraminidase Kim et al., J. Am. Chem. Soc. 119: 681-690 (1997) GS4071 bound to influenza neuraminidase Zanamivir (Relenza®) • active against both influenza A and B •IC50 : 0.21-2.6 ng/ml for influenza neuraminidase • efficacy demonstrated in mouse and ferret models for influenza (upon topical administration) • has to be administered by inhalation : 10 mg bid • therapeutically effective (5 days) : significant reduction in duration of illness • prophylactically effective (4 weeks) : significant reduction in number of ill subjects • well tolerated : clinical adverse events not different from placebo • no evidence for emergence of drug-resistant virus Oseltamivir (Tamiflu®) • active against both influenza A and B •IC50 : < 1 ng/ml for influenza neuraminidase • efficacy demonstrated in mouse and ferret models for influenza (upon oral administration) • can be administered orally : 75 or 150 mg bid • therapeutically effective (5 days) : significant reduction in duration of illness • prophylactically effective (6 weeks) : significant reduction in number of ill subjects • well tolerated : clinical adverse events not different from placebo • no evidence for emergence of drug-resistant virus RESISTANCE MUTATIONS TO NEURAMINIDASE INHIBITORS Neuraminidase 119 Glu → Gly: • specific for zanamivir; • Glu 119 interacts with guanidinium group of zanamivir 292 Arg → Lys: • found for zanamivir; cross-resistance to oseltamivir • Arg 292 interacts with carboxylic acid group of zanamivir and oseltamivir Hemagglutinin Some mutations (i.e. 198 Thr → Ile) diminish affinity of hemagglutinin for its receptor McKimm-Breschkin, Antiviral Res. 47: 1-17 (2000) Benefits offered by neuraminidase inhibitors Therapeutically: • Reduction in illness duration by 1-2 days • Reduction in risk-virus transmission to household or healthcare contacts • Reduction in complications (sinusitis, bronchitis) • Reduction in use of antibiotics Prophylactically: • Seasonal prevention of infection H2NNH O HN OH H H N OH H3C O CH3 CH3 RWJ-270201 Smee et al., Antimicrob. Agents Chemother. 45: 743-748 (2001) Sidwell et al., Antimicrob. Agents Chemother. 45: 749-757 (2001) H3CCH3 ONCH3 FF N F O HO NH2 O A-192558 Wang et al., J. Med. Chem. 44: 1192-1201 (2001) CH3 H H H3C N OH N O H H O H3C O CH3 A-315675 DeGoey et al., J. Org. Chem. 67: 5445-5453 (2002) Hanessian et al., J. Am. Chem. Soc. 124: 4716-4721 (2002) NOH NH2 F N O T-705 T-705 showed potent inhibitory activity against influenza A, B, and C viruses, with 50% effective inhibitory concentrations of 0.013 to 0.48 µg/ml, while it showed no cytotoxicity at concentrations up to 1,000 µg/ml. T-705 was also active against a neuraminidase inhibitor-resistant virus and amantadine-resistant viruses. Furuta et al., Antimicrob. Agents Chemother. 46: 977-981 (2002) HUMAN RHINOVIRUS (HRV) HRV 14 Human rhinovirus type 14 Antirhinoviral targets for therapy Agents can (a) prevent viral attachment to host-cell receptors (ICAM-1 and the low density lipoprotein receptor), (b) inhibit viral uncoating or (c) inhibit viral protein synthesis by blocking 3C viral protease. McKinlay, Curr. Opin. Pharmacol. 1: 477-481 (2001) O C C2H5 H3CO(CHO 2)6 CH C C2H5 O Phenoxyalkyldiketone Arildone WIN38020 De Clercq, In: Antiviral Agents and Human Viral Diseases. Galasso, Whitley & Merigan, eds. Lippincott-Raven Publishers, pp 1-44 (1997) O O N (CH2)7 O N H3C Isoxazole Disoxaril WIN 51711 De Clercq, In: Antiviral Agents and Human Viral Diseases. Galasso, Whitley & Merigan, eds. Lippincott-Raven Publishers, pp 1-44 (1997) CH3 N N H3C O NN Pyridazinamine R61837 De Clercq, In: Antiviral Agents and Human Viral Diseases. Galasso, Whitley & Merigan, eds. Lippincott-Raven Publishers, pp 1-44 (1997) N N O H3CCN(CH2)2 OCO2H5 Phenoxypyridazinamine Pirodavir R77975 De Clercq, In: Antiviral Agents and Human Viral Diseases. Galasso, Whitley & Merigan, eds. Lippincott-Raven Publishers, pp 1-44 (1997) Interaction of WIN 52035 with VP1 of human rhinovirus (HRV-14) Andries, In: Antiviral Chemotherapy. Jeffries & De Clercq, eds. John Wiley & Sons, Chichester, pp 287-319 (1995) Interaction of R61837 with VP1 of human rhinovirus (HRV-14) Andries, In: Antiviral Chemotherapy. Jeffries & De Clercq, eds. John Wiley & Sons, Chichester, pp 287-319 (1995) N CF3 N O O O N Pleconaril (VP-63843) Romero, Exp. Opin. Invest. Drugs 10: 369-379 (2001) BTA188 H3C N NCHO 2 CH3 NN O BTA showed potent in vitro activity against 87 of 100 rhinovirus serotypes with a median EC50 of 10 ng/ml, superior to pleconaril. BTA188 is targeted at the hydrophobic pocket in the core of VP1. Hayden et al., Antiviral Res. 50: A127 (2001) Benzothiazole H3C N N S S S N Benzothiazole targeted at hydrophobic pocket in the core of VP1. EC50 against HRV-14 in cell culture: 0.8 µM. Tsang et al., Chem. Biol. 8: 33-45 (2001) Ruprintrivir O NH O O N N H3C H H N O O O CH2 CH O 3 F Inhibitor of human rhinovirus C3 protease, currently undergoing clinical evaluation for the prevention and treatment of the common cold. Hsyu et al., Antimicrob. Agents Chemother. 46: 392-397 (2002) Pyridone O NH O O N N N H3C H H N O O CH3 O CH O CH3 F F Human rhinovirus (HRV) 3C protease inhibitor showed an average EC50 of 45 nM across 15 serotypes of HRV. Dragovich et al., J. Med. Chem. 45: 1607-1623 (2002) RESPIRATORY SYNCYTIAL VIRUS (RSV) Respiratory Syncytial Virus (RSV) and Parainfluenza Virus (PIV) Hall, N. Engl. J. Med. 344: 1917-1928 (2001) Characteristics of the proteins of respiratory syncytial virus and parainfluenza virus Protein Molecular mass Functions Respiratory Parainfluenza syncytial virus virus kilodaltons Structural protein Surface
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