Synthesis, stability, antiviral activity, and protease-bound structures of substrate-mimicking constrained macrocyclic inhibitors of HIV-1 protease

Tyndall, J. D. A., Reid, R. C., Tyssen, D. P., Jardine, D. K., Todd, B., Passmore, M., March, D. R., Pattenden, L., Bergman, D. A., Alewood, D., Hu, S., Alewood, P.F., Birch, C. J., Martin, J. L. and Fairlie, D. (2000) Synthesis, stability, antiviral activity, and protease-bound structures of substrate-mimicking constrained macrocyclic inhibitors of HIV-1 protease. Journal of Medicinal Chemistry, 43 19: 3495-3504. doi:10.1021/jm000013n


Author Tyndall, J. D. A.
Reid, R. C.
Tyssen, D. P.
Jardine, D. K.
Todd, B.
Passmore, M.
March, D. R.
Pattenden, L.
Bergman, D. A.
Alewood, D.
Hu, S.
Alewood, P.F.
Birch, C. J.
Martin, J. L.
Fairlie, D.
Title Synthesis, stability, antiviral activity, and protease-bound structures of substrate-mimicking constrained macrocyclic inhibitors of HIV-1 protease
Journal name Journal of Medicinal Chemistry   Check publisher's open access policy
ISSN 0022-2623
Publication date 2000-01-01
Sub-type Article (original research)
DOI 10.1021/jm000013n
Volume 43
Issue 19
Start page 3495
End page 3504
Total pages 10
Place of publication USA
Publisher American Chemical Society
Collection year 2001
Language eng
Subject C1
250204 Bioinorganic Chemistry
730102 Immune system and allergy
Abstract Three new peptidomimetics (1-3) have been developed with highly stable and conformationally constrained macrocyclic components that replace tripeptide segments of protease substrates. Each compound inhibits both HIV-1 protease and viral replication (HIV-I, HIV-2) at nanomolar concentrations without cytotoxicity to uninfected cells below 10 mu M. Their activities against HIV-1 protease (K-i 1.7 nM (1), 0.6 nM (2), 0.3 nM (3)) are 1-2 orders of magnitude greater than their antiviral potencies against HIV-1-infected primary peripheral blood mononuclear cells (IC50 45 nM (1), 56 nM (2), 95 nM (3)) or HIV-1-infected MT2 cells (IC50 90 nM (1), 60 nM (2)), suggesting suboptimal cellular uptake. However their antiviral potencies are similar to those of indinavir and amprenavir under identical conditions. There were significant differences in their capacities to inhibit the replication of HIV-1 and HIV-2 in infected MT2 cells, 1 being ineffective against HIV-2 while 2 was equally effective against both virus types. Evidence is presented that 1 and 2 inhibit cleavage of the HIV-1 structural protein precursor Pr55(gag) to p24 in virions derived from chronically infected cells, consistent with inhibition of the viral protease in cells. Crystal structures refined to 1.75 Angstrom (1) and 1.85 Angstrom (2) for two of the macrocyclic inhibitors bound to HIV-1 protease establish structural mimicry of the tripeptides that the cycles were designed to imitate. Structural comparisons between protease-bound macrocyclic inhibitors, VX478 (amprenavir), and L-735,524 (indinavir) show that their common acyclic components share the same space in the active site of the enzyme and make identical interactions with enzyme residues. This substrate-mimicking minimalist approach to drug design could have benefits in the context of viral resistance, since mutations which induce inhibitor resistance may also be those which prevent substrate processing.
Keyword Chemistry, Medicinal
Immunodeficiency-virus Infection
Orally Bioavailable Inhibitor
Peptidomimetic Inhibitors
Kinetic-properties
Crystal-structure
Binding Mode
Drug-design
Enzyme
Complex
Errors
Q-Index Code C1

Document type: Journal Article
Sub-type: Article (original research)
Collection: Institute for Molecular Bioscience - Publications
 
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Created: Wed, 15 Aug 2007, 05:40:23 EST