Synthesis and evaluation of tripeptidyl α-Ketoamides as human rhinovirus 3C protease inhibitors

Abstract We describe herein the synthesis and biological evaluation of a series of tripeptidyl α-ketoamides as human rhinovirus (HRV) 3C protease inhibitors. The most potent inhibitor discussed in this manuscript, 4I, exhibited impressive enzyme inhibitory activity as well as antiviral activity against HRV-14.

[1]  B. Heinz,et al.  Glutamine-derived aldehydes for the inhibition of human rhinovirus 3C protease , 1995 .

[2]  E. Hébert,et al.  Maximum optical rotation of 2-fluorooctane? A survey of fluorinating reagents , 1979 .

[3]  D. Barton,et al.  A new method for the deoxygenation of secondary alcohols , 1975 .

[4]  D. Le-Nguyen,et al.  PyBOP®: A new peptide coupling reagent devoid of toxic by-product , 1990 .

[5]  J. Monn,et al.  A Concise, Stereocontrolled Thiazolium Ylide Approach to Kainic Acid , 1994 .

[6]  P. Dragovich Recent advances in the development of human rhinovirus 3C protease inhibitors , 2001 .

[7]  N. Roehm,et al.  An improved colorimetric assay for cell proliferation and viability utilizing the tetrazolium salt XTT. , 1991, Journal of immunological methods.

[8]  D. Matthews,et al.  Tripeptide aldehyde inhibitors of human rhinovirus 3C protease: design, synthesis, biological evaluation, and cocrystal structure solution of P1 glutamine isosteric replacements. , 1998, Journal of medicinal chemistry.

[9]  D. Matthews,et al.  Structure-based design of ketone-containing, tripeptidyl human rhinovirus 3C protease inhibitors. , 2000, Bioorganic & medicinal chemistry letters.

[10]  M. Xian,et al.  S-nitrosothiols as novel, reversible inhibitors of human rhinovirus 3C protease. , 2000, Bioorganic & medicinal chemistry letters.

[11]  S. Venkatraman,et al.  Design, synthesis, and evaluation of azapeptides as substrates and inhibitors for human rhinovirus 3C protease. , 1999, Bioorganic & medicinal chemistry letters.

[12]  D. Norbeck,et al.  Inhibition of 3C protease from human rhinovirus strain 1B by peptidyl bromomethylketonehydrazides. , 1999, Archives of biochemistry and biophysics.

[13]  D. Matthews,et al.  Structure-based design, synthesis, and biological evaluation of irreversible human rhinovirus 3C protease inhibitors. 4. Incorporation of P1 lactam moieties as L-glutamine replacements. , 1999, Journal of medicinal chemistry.

[14]  D. Matthews,et al.  Structure-based design, synthesis, and biological evaluation of irreversible human rhinovirus 3C protease inhibitors. 3. Structure-activity studies of ketomethylene-containing peptidomimetics. , 1999, Journal of medicinal chemistry.

[15]  A. Porter Picornavirus nonstructural proteins: emerging roles in virus replication and inhibition of host cell functions , 1993, Journal of virology.

[16]  R. Loncharich,et al.  A continuous colorimetric assay for rhinovirus-14 3C protease using peptide p-nitroanilides as substrates. , 1997, Analytical biochemistry.

[17]  D. Dess,et al.  Readily accessible 12-I-5 oxidant for the conversion of primary and secondary alcohols to aldehydes and ketones , 1983 .

[18]  S. Venkatraman,et al.  Synthesis and evaluation of peptidyl Michael acceptors that inactivate human rhinovirus 3C protease and inhibit virus replication. , 1998, Journal of medicinal chemistry.

[19]  A. El‐Faham,et al.  The diisopropylcarbodiimide/ 1-hydroxy-7-azabenzotriazole system: Segment coupling and stepwise peptide assembly , 1999 .

[20]  D. Matthews,et al.  Structure of human rhinovirus 3C protease reveals a trypsin-like polypeptide fold, RNA-binding site, and means for cleaving precursor polyprotein , 1994, Cell.

[21]  T. Shepherd,et al.  Small peptidic aldehyde inhibitors of human rhinovirus 3C protease , 1996 .