Structure-based design, synthesis, and biological evaluation of irreversible human rhinovirus 3C protease inhibitors. 1. Michael acceptor structure-activity studies

P S Dragovich; S E Webber; R E Babine; S A Fuhrman; A K Patick; D A Matthews; C A Lee; S H Reich; T J Prins; J T Marakovits; E S Littlefield; R Zhou; J Tikhe; C E Ford; M B Wallace; J W Meador 3rd; R A Ferre; E L Brown; S L Binford; J E Harr; D M DeLisle; S T Worland

doi:10.1021/jm980068d

Structure-based design, synthesis, and biological evaluation of irreversible human rhinovirus 3C protease inhibitors. 1. Michael acceptor structure-activity studies

J Med Chem. 1998 Jul 16;41(15):2806-18. doi: 10.1021/jm980068d.

Affiliation

¹ Agouron Pharmaceuticals, Inc., 3565 General Atomics Court, San Diego, California 92121, USA.

PMID: 9667970
DOI: 10.1021/jm980068d

Abstract

The structure-based design, chemical synthesis, and biological evaluation of peptide-derived human rhinovirus (HRV) 3C protease (3CP) inhibitors are described. These compounds incorporate various Michael acceptor moieties and are shown to irreversibly bind to HRV serotype 14 3CP with inhibition activities (kobs/[I]) ranging from 100 to 600 000 M-1 s-1. These inhibitors are also shown to exhibit antiviral activity when tested against HRV-14-infected H1-HeLa cells with EC50's approaching 0.50 microM. Extensive structure-activity relationships developed by Michael acceptor alteration are reported along with the evaluation of several compounds against HRV serotypes other than 14. A 2.0 A crystal structure of a peptide-derived inhibitor complexed with HRV-2 3CP is also detailed.

Publication types

Comparative Study

MeSH terms

3C Viral Proteases
Animals
Antiviral Agents* / chemical synthesis
Antiviral Agents* / chemistry
Antiviral Agents* / metabolism
Antiviral Agents* / pharmacology
Binding Sites
Cell Line, Transformed
Crystallography, X-Ray
Cysteine Endopeptidases / chemistry
Cysteine Endopeptidases / metabolism*
Cysteine Proteinase Inhibitors* / chemical synthesis
Cysteine Proteinase Inhibitors* / chemistry
Cysteine Proteinase Inhibitors* / metabolism
Cysteine Proteinase Inhibitors* / pharmacology
Drug Design*
Drug Stability
HeLa Cells
Humans
Oligopeptides* / chemical synthesis
Oligopeptides* / chemistry
Oligopeptides* / metabolism
Oligopeptides* / pharmacology
Protein Conformation
Rats
Rats, Sprague-Dawley
Rhinovirus / drug effects*
Rhinovirus / enzymology
Structure-Activity Relationship
Viral Proteins*

Substances

Antiviral Agents
Cysteine Proteinase Inhibitors
Oligopeptides
Viral Proteins
Cysteine Endopeptidases
3C Viral Proteases