Protease inhibitors design

The discovery of yet other nonhydrolyzable amide bond isosteres has particularly impacted the design of protease inhibitors, and these include hydroxymethylene or FfCF OH)], 12 hydroxyethylene or T fCF OFQCFy and T fCFkCHiOH)], 13 and 14, respectively dihydroxyethylene or ( [ )], 15, hydroxyethylamine or 4 [CH(0H)CH2N], 16, dihydroxyethylene 17 and C2-symmetric hydroxymethylene 18. In the specific case of aspartyl protease inhibitor design (see below) such backbone modifications have been extremely effective, as they may represent transition state mimics or bioisosteres of the hypothetical tetrahedral intermediate (e.g., xF[C(OH)2NH] for this class of proteolytic enzymes. 

A second example of protease inhibitor design that properly illustrates the peptide scaffold-based approach is that of thrombin inhibitors. Work with these compounds led to the identification of highly potent, selective, and in vivo-effective lead compounds. A member of the serine protease family, thrombin cleaves a number of substrates (e.g., fibrinogen) and activates its platelet receptor (a G-protein-coupled receptor) by proteolysis of the extracellular N-terminal domain which results in self-activation (for a review see Reference 66). Initial lead inhibitors of thrombin were substrate-based, including the fibrinogen P3-Pi Phe-Pro-Arg sequence [67] and simple Arg derivatives such as Tos-Arg-OMe [68]. 

Based Free Energy Parameterization of Enzyme-Inhibitor Binding. Application to FDV-1-Protease Inhibitor Design. 

Figure 28-26 Saquinavir (Fortovase, Invjrase), 15, was th first HIV-1 protease inhibitor designed with structure-based CADD methods to receive FDA approval. Mere saquinavir is shown inside the binding cavity of HIV-1.

The capability to communicate 3D structural studies with the chemists and other researchers has evolved significantly [80]. Today in our laboratories, the use of a 3D projection room has advanced the HIV-1 protease inhibitor design to a team effort, in which creative design ideas can be discussed within a group in an extremely productive manner, while visualizing the protein/inhibitor interactions. 

Specker, E., Bottcher, J., Brass, S., Heine, A., Lilie, H., Schoop, A., Muller, G., Griebenow, N., Klebe, G. Unexpected novel binding mode of pyrrolidine-based aspartyl protease inhibitors design, synthesis and crystal structure in complex with HIV protease. Chem. Med. Chem. 2006, 1, 106-117. 

HIV protease inhibitor design. Compoumi A isoneol a series that were designed to be potent inhibitors of HIV protease. 

Wallqvist, A., Jernigan, R. L. Covell, D. G. (1995). A preference-based free-energy parameterization of enzyme-inhibitor binding. Applications to HIV-l-protease inhibitor design. Protein Science 4, 1881-1903. 

Ritonavir is a peptidomimetic HIV protease inhibitor designed to complement the C2- symmetry of the enzyme active site. Ritonavir is active against both HIV-1 and HIV-2, althongh it may be slightly less active against the latter. Its IC50 for wild-type HIV-1 variants in the absence of hnman sernm ranges from 4 to 150 nM. 

Ripka, A.S., Satyshur, K.A., Bohacek, R.S. and Rich, D.H. (2001) Aspartic protease inhibitors designed from computer-generated templates bind as predicted. Org. Lett. 3 2309-2312. 

Smith, A.B., Hirschmann, R., Pasternak, A., Guzman, M.C., Yokoyama, A., et al. (1995) Pyrrolinone-based HTV protease inhibitors. Design, synthesis, and antiviral activity evidence for improved transport. J. Am. Chem. Soc. 117 11113-11123. 

A. Wallqvist, R. L. Jernigan, and D. G. Covell, Protein Sei., 4, 1881 (1995). A Preference-Based Free-Energy Parameterization of Enzyme Inhibitor Binding. Applications to HIV-1 Protease Inhibitor Design. 

The article by Hutchby et alf prompted a commentary that discussed the energetics of the process and pointed up its exciting potential in the field of peptide/protein ligation and protease inhibitor design. 

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