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Design, Synthesis, and Evaluation of Nonpeptidic Inhibitors of Human Rhinovirus 3C Protease

Webber, Stephen E. ; Tikhe, Jayashree ; Worland, Stephen T. ; Fuhrman, Shella A. ; Hendrickson, Thomas F. ; Matthews, David A. ; Love, Robert A. ; Patick, Amy K. ; Meador, James W. ; Ferre, Rose Ann ; Brown, Edward L. ; DeLisle, Dorothy M. ; Ford, Clifford E. ; Binford, Susan L.

Journal of medicinal chemistry, 1996-12, Vol.39 (26), p.5072-5082 [Periódico revisado por pares]

Washington, DC: American Chemical Society

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Título:
Design, Synthesis, and Evaluation of Nonpeptidic Inhibitors of Human Rhinovirus 3C Protease
Autor: Webber, Stephen E. ; Tikhe, Jayashree ; Worland, Stephen T. ; Fuhrman, Shella A. ; Hendrickson, Thomas F. ; Matthews, David A. ; Love, Robert A. ; Patick, Amy K. ; Meador, James W. ; Ferre, Rose Ann ; Brown, Edward L. ; DeLisle, Dorothy M. ; Ford, Clifford E. ; Binford, Susan L.
Assuntos: 3C Viral Proteases ; Antibiotics. Antiinfectious agents. Antiparasitic agents ; Antiviral agents ; Antiviral Agents - chemical synthesis ; Antiviral Agents - chemistry ; Antiviral Agents - pharmacology ; Biological and medical sciences ; Cysteine Endopeptidases - chemistry ; Cysteine Endopeptidases - drug effects ; HeLa Cells ; human rhinovirus ; Humans ; Magnetic Resonance Spectroscopy ; Mass Spectrometry ; Medical sciences ; Molecular Structure ; Pharmacology. Drug treatments ; Protease Inhibitors - chemical synthesis ; Protease Inhibitors - chemistry ; Protease Inhibitors - pharmacology ; Thermodynamics ; Viral Proteins
É parte de: Journal of medicinal chemistry, 1996-12, Vol.39 (26), p.5072-5082
Notas: ark:/67375/TPS-X9H8Z9SH-W
Abstract published in Advance ACS Abstracts, November 15, 1996.
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Descrição: The design, synthesis, and biological evaluation of reversible, nonpeptidic inhibitors of human rhinovirus (HRV) 3C protease (3CP) are reported. A novel series of 2,3-dioxindoles (isatins) were designed that utilized a combination of protein structure-based drug design, molecular modeling, and structure−activity relationship (SAR). The C-2 carbonyl of isatin was envisioned to react in the active site of HRV 3CP with the cysteine responsible for catalytic proteolysis, thus forming a stabilized transition state mimic. Molecular-modeling experiments using the apo crystal structure of human rhinovirus-serotype 14 (HRV-14) 3CP and a peptide substrate model allowed us to design recognition features into the P1 and P2 subsites, respectively, from the 5- and 1-positions of isatin. Attempts to optimize recognition properties in the P1 subsite using SAR at the 5-position were performed. In addition, a series of ab initio calculations were carried out on several 5-substituted isatins to investigate the stability of sulfide adducts at C-3. The inhibitors were prepared by general synthetic methods, starting with commercially available 5-substituted isatins in nearly every case. All compounds were tested for inhibition of purified HRV-14 3CP. Compounds 8, 14, and 19 were found to have excellent selectivity for HRV-14 3CP compared to other proteolytic enzymes, including chymotrypsin and cathepsin B. Selected compounds were assayed for antiviral activity against HRV-14-infected HI-HeLa cells. A 2.8 Å cocrystal structure of derivative 19 covalently bound to human rhinovirus-serotype 2 (HRV-2) 3CP was solved and revealed that the isatin was situated in essentially the same conformation as modeled.
Editor: Washington, DC: American Chemical Society
Idioma: Inglês

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Design, Synthesis, and Evaluation of Nonpeptidic Inhibitors of Human Rhinovirus 3C Protease

Webber, Stephen E. ; Tikhe, Jayashree ; Worland, Stephen T. ; Fuhrman, Shella A. ; Hendrickson, Thomas F. ; Matthews, David A. ; Love, Robert A. ; Patick, Amy K. ; Meador, James W. ; Ferre, Rose Ann ; Brown, Edward L. ; DeLisle, Dorothy M. ; Ford, Clifford E. ; Binford, Susan L.

Washington, DC: American Chemical Society

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