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Biochemistry 1993 Aug 10;32(31):7972-80

Inhibition of human immunodeficiency virus-1 protease by a C2-symmetric phosphinate. Synthesis and crystallographic analysis.

Abdel-Meguid SS, Zhao B, Murthy KH, Winborne E, Choi JK, DesJarlais RL, Minnich MD, Culp JS, Debouck C, Tomaszek TA Jr, et al

Department of Macromolecular Sciences, SmithKline Beecham, King of Prussia, Pennsylvania 19406.

The human immunodeficiency virus type 1 (HIV-1) protease is a potential target of acquired immune deficiency syndrome (AIDS) therapy. A highly potent, perfectly symmetrical phosphinate inhibitor of this enzyme, SB204144, has been synthesized. It is a competitive inhibitor of HIV-1 protease, with an apparent inhibition constant of 2.8 nM at pH 6.0. The three-dimensional structure of SB204144 bound to the enzyme has been determined at 2.3-A resolution by X-ray diffraction techniques and refined to a crystallographic discrepancy factor, R (= sigma parallel F(o) magnitude to - Fc parallel/sigma magnitude of F(o)), of 0.178. The inhibitor is held in the enzyme active site by a set of hydrophobic and hydrophilic interactions, including an interaction between Arg8 and the center of the terminal benzene rings of the inhibitor. The phosphinate establishes a novel interaction with the two catalytic aspartates; each oxygen of the central phosphinic acid moiety interacts with a single oxygen of one aspartic acid, establishing a very short (2.2-2.4 A) oxygen-oxygen contact. As with the structures of penicillopepsin bound to phosphinate and phosphonate inhibitors [Fraser, M. E., Strynadka, N. C., Bartlett, P. A., Hanson, J. E., & James, M. N. (1992) Biochemistry 31, 5201-14], we interpret this short distance and the stereochemical environment of each pair of oxygens in terms of a hydrogen bond that has a symmetric single-well potential energy curve with the proton located midway between the two atoms.

MeSH Terms:

• Amino Acid Sequence
• Binding Sites
• Catalysis/drug effects
• Crystallization
• HIV Protease/metabolism
• HIV Protease Inhibitors/metabolism
• HIV Protease Inhibitors/chemical synthesis*
• HIV Protease Inhibitors/chemistry
• HIV-1/enzymology*
• Models, Molecular
• Molecular Conformation
• Molecular Sequence Data
• Organophosphorus Compounds/metabolism
• Organophosphorus Compounds/chemical synthesis*
• Organophosphorus Compounds/chemistry
• Protein Binding
• Recombinant Proteins/metabolism
• Sugar Alcohols/chemistry
• Valine/metabolism
• Valine/chemical synthesis
• Valine/chemistry
• Valine/analogs & derivatives*
• X-Ray Diffraction

Substances:

• Valine
• SB 204144
• A 74704
• Sugar Alcohols
• Recombinant Proteins
• Organophosphorus Compounds
• HIV Protease Inhibitors
• HIV Protease

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