Structure of the HIV-1 integrase catalytic domain complexed with an inhibitor: A platform for antiviral drug design

Abstract

HIV integrase, the enzyme that inserts the viral DNA into the host chromosome, has no mammalian counterpart, making it an attractive target for antiviral drug design. As one of the three enzymes produced by HIV, it can be expected that inhibitors of this enzyme will complement the therapeutic use of HIV protease and reverse transcriptase inhibitors. We have determined the structure of a complex of the HIV-1 integrase core domain with a novel inhibitor, 5ClTEP, 1-(5-chloroindol-3-yl)-3-hydroxy-3-(2H-tetrazol-5-yl)-propenone, to 2.1-Å resolution. The inhibitor binds centrally in the active site of the integrase and makes a number of close contacts with the protein. Only minor changes in the protein accompany inhibitor binding. This inhibitor complex will provide a platform for structure-based design of an additional class of inhibitors for antiviral therapy.

Crystal structure of (Z)-1-(1,5-dimethyl-1H-pyrazol-3-yl)-3-hydroxybut-2-en-1-one C9H12N2O2

“…Their versatile utility in medicinal chemistry is rmly established including anti-HIV [1,2], antitumor [3][4][5], anti-in uenza [6], antioxidant [7], and anti-in ammatory [8] activities. In this study we coupled ethyl pyrazole carboxylate with acetone to produce the title compound in acceptable yield.…”

Human Immunodeficiency Virus Type 1 (HIV-1) Integrase: Resistance to Diketo Acid Integrase Inhibitors Impairs HIV-1 Replication and Integration and Confers Cross-Resistance to l -Chicoric Acid

“…The data on cross-resistance between the diketo acids and dicaffeoyltartaric acids are intriguing given the cocrystal studies published for the IN inhibitor 5-CITEP with the catalytic core of IN (27). No computer modeling studies with L-731,988 have been published to date; however, given the structural similarities between 5-CITEP and L-731,988 (56) (see structures above) and the similarity of binding by 5-CITEP and L-CA into an inhibitor-binding pocket, it is reasonable to hypothesize that all three may bind a similar pocket.…”

The Terminal (Catalytic) Adenosine of the HIV LTR Controls the Kinetics of Binding and Dissociation of HIV Integrase Strand Transfer Inhibitors

“…The assembly of IN onto the viral LTR stimulates the high affinity binding of STIs, suggesting that the binding pocket for these inhibitors is derived from a specific structural arrangement of the nucleoprotein complex (3)(4)(5)(14)(15)(16)(17)(18)(19)(20)(21). Published models of HIV IN (19,22) suggest that these specific STIs bind to the IN active site in a pocket flanked by the end of the LTR such that the diketoacid moiety, or its mimic, is positioned to coordinate with both of the catalytic magnesium atoms (23)(24)(25) (14,19,22,(26)(27)(28)(29).…”