Structure-based design of irreversible, tripeptidyl human rhinovirus 3C protease inhibitors containing N-methyl amino acids

P S Dragovich; S E Webber; T J Prins; R Zhou; J T Marakovits; J G Tikhe; S A Fuhrman; A K Patick; D A Matthews; C E Ford; E L Brown; S L Binford; J W Meador 3rd; R A Ferre; S T Worland

doi:10.1016/s0960-894x(99)00368-6

Structure-based design of irreversible, tripeptidyl human rhinovirus 3C protease inhibitors containing N-methyl amino acids

Bioorg Med Chem Lett. 1999 Aug 2;9(15):2189-94. doi: 10.1016/s0960-894x(99)00368-6.

Authors

P S Dragovich¹, S E Webber, T J Prins, R Zhou, J T Marakovits, J G Tikhe, S A Fuhrman, A K Patick, D A Matthews, C E Ford, E L Brown, S L Binford, J W Meador 3rd, R A Ferre, S T Worland

Affiliation

¹ Agouron Pharmaceuticals, Inc., San Diego, CA 92121, USA.

PMID: 10465543
DOI: 10.1016/s0960-894x(99)00368-6

Abstract

Tripeptide-derived molecules incorporating N-methyl amino acid residues and C-terminal Michael acceptor moieties were evaluated as irreversible inhibitors of the cysteine-containing human rhinovirus 3C protease (3CP). Such compounds displayed good 3CP inhibition activity (k(obs)/[I] up to 610,000 M(-1) s(-1)) and potent in vitro antiviral properties (EC50 approaching 0.03 microM) when tested against HRV serotype-14.

MeSH terms

3C Viral Proteases
Cysteine Endopeptidases / drug effects
Cysteine Endopeptidases / metabolism*
Drug Design
Humans
Peptides / chemical synthesis
Peptides / pharmacology
Protease Inhibitors / chemical synthesis*
Protease Inhibitors / pharmacology
Rhinovirus / drug effects
Rhinovirus / enzymology*
Structure-Activity Relationship
Viral Proteins*

Substances

Peptides
Protease Inhibitors
Viral Proteins
Cysteine Endopeptidases
3C Viral Proteases