Design of translactam HCMV protease inhibitors as potent antivirals
Identifieur interne : 003003 ( Main/Exploration ); précédent : 003002; suivant : 003004Design of translactam HCMV protease inhibitors as potent antivirals
Auteurs : Alan D. Borthwick [Royaume-Uni]Source :
- Medicinal Research Reviews [ 0198-6325 ] ; 2005-07.
English descriptors
- Teeft :
- Active site, Acylated, Acylation, Amide, Analog, Antiviral, Antiviral activity, Assay, Benzothiazole, Benzothiazole ring, Borthwick, Capsid, Carbonyl, Catalytic triad, Chem, Chem lett, Cleavage, Crystal structure, Cytomegalovirus, Dala, Dala hcmv protease, Derivative, Enzyme, Exall, Good brain, Hcmv, Hcmv dala protease, Hcmv protease, Hcmv protease inhibitors, Hcmv translactam template, Herpes, Herpes protease, Herpes viruses, Herpesvirus, Human cytomegalovirus, Human cytomegalovirus protease, Human plasma, Inhibitor, Internal cleavage site, Lactam, Lactam carbonyl, Lactam nitrogen, Lantana camara, Medicinal chemistry, Methyl, Methyl group, Methyl substituent, Molecular weight, Monocyclic, Natural substrate, Novel inhibitors, Ocular penetration, Peptide, Pharmacokinetics, Phenyl, Plasma stability, Proline, Proline ring, Protease, Protease inhibitors, Pyrrolidine, Release site, Ring closure, Ring system, Scaffold protein, Serine, Serine protease, Serine proteases, Stereochemistry, Substituent, Substituents, Sulfonamide, Template, Translactam, Translactam hcmv protease inhibitors, Triad, Urea, Vero cell, Viral, Viral enzyme, Viral protease, Weingarten.
Abstract
Human cytomegalovirus (HCMV) is an important pathogen for which there is a significant unmet medical need. New HCMV antivirals, active against novel molecular targets, are undoubtedly needed as the currently available drugs ganciclovir, cidofovir, and foscarnet, which are all viral DNA inhibitors, suffer from limited effectiveness, mainly due to the development of drug resistance, poor bioavailability, and toxicity. One of the newer molecular targets that has been exploited in the search for better drug candidates is HCMV protease. Our δAla HCMV protease (wild type variant with the internal cleavage site deleted) was cloned and expressed in E. coli. This viral enzyme was used to develop HCMV protease assays to evaluate potential inhibitors. The chirally pure (SRS)‐α‐methyl pyrrolidine‐5,5‐trans‐lactam template was synthesized, which together with the natural substrate requirements of HCMV protease and detailed SAR, was used to design potent and selective mechanism based inhibitors of HCMV protease. The mechanism of action of these inhibitors of HCMV protease was investigated by ESI/MS, and the X‐ray crystal structure of the HCMV protease was used to refine our selective viral enzyme inhibitors to obtain plasma stable antivirals. A novel ELISA antiviral assay was developed which, together with a cytotoxicity assay, enabled us to discover anti‐HCMV drug candidates equivalent in potency to ganciclovir that had good pharmacokinetics in the dog and good brain and ocular penetration in the guinea pig. © 2005 Wiley Periodicals, Inc. Med Res Rev.
Url:
DOI: 10.1002/med.20030
Affiliations:
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Le document en format XML
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<front><div type="abstract" xml:lang="en">Human cytomegalovirus (HCMV) is an important pathogen for which there is a significant unmet medical need. New HCMV antivirals, active against novel molecular targets, are undoubtedly needed as the currently available drugs ganciclovir, cidofovir, and foscarnet, which are all viral DNA inhibitors, suffer from limited effectiveness, mainly due to the development of drug resistance, poor bioavailability, and toxicity. One of the newer molecular targets that has been exploited in the search for better drug candidates is HCMV protease. Our δAla HCMV protease (wild type variant with the internal cleavage site deleted) was cloned and expressed in E. coli. This viral enzyme was used to develop HCMV protease assays to evaluate potential inhibitors. The chirally pure (SRS)‐α‐methyl pyrrolidine‐5,5‐trans‐lactam template was synthesized, which together with the natural substrate requirements of HCMV protease and detailed SAR, was used to design potent and selective mechanism based inhibitors of HCMV protease. The mechanism of action of these inhibitors of HCMV protease was investigated by ESI/MS, and the X‐ray crystal structure of the HCMV protease was used to refine our selective viral enzyme inhibitors to obtain plasma stable antivirals. A novel ELISA antiviral assay was developed which, together with a cytotoxicity assay, enabled us to discover anti‐HCMV drug candidates equivalent in potency to ganciclovir that had good pharmacokinetics in the dog and good brain and ocular penetration in the guinea pig. © 2005 Wiley Periodicals, Inc. Med Res Rev.</div>
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