1. Structure-based design, synthesis, and biological evaluation of irreversible human rhinovirus 3C protease inhibitors. 2. Peptide structure-activity studies.
- Author
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Dragovich PS, Webber SE, Babine RE, Fuhrman SA, Patick AK, Matthews DA, Reich SH, Marakovits JT, Prins TJ, Zhou R, Tikhe J, Littlefield ES, Bleckman TM, Wallace MB, Little TL, Ford CE, Meador JW 3rd, Ferre RA, Brown EL, Binford SL, DeLisle DM, and Worland ST
- Subjects
- 3C Viral Proteases, Binding Sites, Cell Line, Transformed, Crystallography, X-Ray, Cysteine Endopeptidases chemistry, Drug Evaluation, Preclinical, Humans, Rhinovirus enzymology, Structure-Activity Relationship, Antiviral Agents chemical synthesis, Antiviral Agents chemistry, Antiviral Agents metabolism, Antiviral Agents pharmacology, Cysteine Endopeptidases metabolism, Cysteine Proteinase Inhibitors chemical synthesis, Cysteine Proteinase Inhibitors chemistry, Cysteine Proteinase Inhibitors metabolism, Cysteine Proteinase Inhibitors pharmacology, Drug Design, Oligopeptides chemical synthesis, Oligopeptides chemistry, Oligopeptides metabolism, Oligopeptides pharmacology, Rhinovirus drug effects, Viral Proteins
- Abstract
The structure-based design, chemical synthesis, and biological evaluation of various peptide-derived human rhinovirus (HRV) 3C protease (3CP) inhibitors are described. These compounds are comprised of an ethyl propenoate Michael acceptor moiety and a tripeptidyl binding determinant. The systematic modification of each amino acid residue present in the binding determinant as well as the N-terminal functionality is described. Such modifications are shown to provide irreversible HRV-14 3CP inhibitors with anti-3CP activities (kobs/[I]) ranging from 60 to 280 000 M-1 s-1 and antiviral EC50's which approach 0.15 microM. An optimized inhibitor which incorporates several improvements identified by the structure-activity studies is also described. This molecule displays very rapid irreversible inhibition of HRV-14 3CP (kobs/[I] = 800 000 M-1 s-1) and potent antiviral activity against HRV-14 in cell culture (EC50 = 0.056 microM). A 1.9 A crystal structure of an S-alkylthiocarbamate-containing inhibitor complexed with HRV-2 3CP is also detailed.
- Published
- 1998
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