Protease Inhibitors:  Current Status and Future Prospects

Abstract

in 1997. She is currently completing her Ph.D. degree in the Centre for Drug Design and Development. Her Ph.D. studies are directed at designing and developing competitive reversible protease inhibitors, particularly for serine and cysteine proteases involved in viral and parasitic infections, Alzheimer's disease, and apoptosis. Giovanni (John) Abbenante received his B.Sc. (Hons) degree from the Department of Chemistry of the University of Adelaide and his Ph.D. degree on the synthesis of GABA b receptor antagonists from Flinders University in 1992. He undertook postdoctoral studies on the synthesis of ladderanes at Central Queensland University and of HIV-1 protease inhibitors at the University of Queensland. He is currently a Senior Research Officer in the Chemistry Group of the Centre for Drug Design and Development with interests in drug design and in the synthesis of protease inhibitors, macrocycles, receptor antagonists, and peptidomimetics. David P. Fairlie received a B.Sc. (Hons) degree from the University of Adelaide and a Ph.D. from the University of South Wales and did postdoctoral research at Stanford University and University of Toronto. He has held research/ teaching appointments in six Australian universities and has led the Chemistry Group in the Centre for Drug Design and Development since 1991. He is Scientific Director of Promics Pty Ltd. Research interests are in chemical synthesis (organic, inorganic), molecular recognition (DNA-, RNA-, protein-, metalbinding compounds), peptide and protein mimetics, enzyme inhibitors and receptor antagonists for viral infections, inflammatory disorders, cancers, and neurodegenerative diseases, and in mechanisms of chemical reactions, biological processes, disease development, and drug action.

Chemical genetic strategy for targeting protein kinases based on covalent complementarity

“…However, under similar conditions, we did not observe adduct formation with 13, possibly due to a reversible covalent interaction. These types of interactions are well documented for several types of electrophilic protease inhibitors (30). The results suggest that covalent binding of the electrophilic inhibitors depend on the presence of a cysteine gatekeeper and we will hereafter refer to T338C c-Src as electrophilesensitive c-Src1 (c-Src-ES1).…”

Enzymatic Characterization and Homology Model of a Catalytically Active Recombinant West Nile Virus NS3 Protease

“…A four-residue P3-P1Ј substrate (Thr-Lys-Arg-Gly) was docked into the active site of a homology model of the WNV NS3 protease using GOLD v2.1 (21). A specified distance constraint between substrate residue Arg (P1) and WNV protease Tyr 150 (S1), as well as distance and hydrogen bond constraints between substrate residue Thr (P3) and WNV protease Gly 153 (S3) were used based on our understanding of protease-inhibitor interactions (22,23). 3 The docked structures were ranked for best fitting conformations using GOLD 2.1 (21).…”

The efficiency of C-4 substituents in activating the β-lactam scaffold towards serine proteases and hydroxide ion

“…[1][2][3][4][5][6][7] The efficiency of β-lactams as enzyme inhibitors depends on the molecular recognition by the protein as well as on the intrinsic chemical reactivity of the β-lactam, both of which affect the rate at which these inhibitors acylate the serine residue. 8 Among the most extensively studied enzymatic reactions of β-lactams is the inhibition of class A β-lactamases by penam sulfone inhibitors such as sulbactam, 1 (Scheme 1), tazobactam and their analogues.…”