HIV integrase is a rational target for treating HIV infection and preventing AIDS. It took approximately 12 years to develop clinically usable inhibitors of integrase, and Phase I clinical trials of integrase inhibitors have just begun. This review focuses on the molecular basis and rationale for developing integrase inhibitors. The main classes of lead compounds are also described, as well as the concept of interfacial inhibitors of protein–nucleic-acid interactions that might apply to the clinically used strand-transfer inhibitors.

Integrase inhibitors to treat HIV/AIDS

HIV integrase is a rational target for treating HIV infection and preventing AIDS. It took approximately 12 years to develop clinically usable inhibitors of integrase, and Phase I clinical trials of integrase inhibitors have just begun. This review focuses on the molecular basis and rationale for developing integrase inhibitors. The main classes of lead compounds are also described, as well as the concept of interfacial inhibitors of protein-nucleic-acid interactions that might apply to the clinically used strand-transfer inhibitors.

https://www.discover.nci.nih.gov/pommier/2005.Pommier.nrd.pdf

Integrase inhibitors to treat HIV/AIDS.

Strand transfer inhibitors of HIV-1 integrase: bringing IN a new era of antiretroviral therapy.

Discovery of diketoacid-containing compounds as HIV-1 integrase (IN) inhibitors played a major role in validating this enzyme as an important target for the development of therapeutics against HIV infection. In fact, S-1360, the first clinically used IN inhibitor containing a triazole ring as a bioisostere of a carboxylic acid moiety belongs to this class of compounds. To understand the role of divalent metal-chelating in the inhibition of IN (J. Med. Chem. 2002, 45, 5661−5670), we designed and synthesized a series of novel dimeric diketo-containing compounds with the notion that such dimeric compounds may simultaneously bind to two divalent metal ions on the active site of IN. We rationalized that the two diketo subunits separated by uniquely designed linkers can potentially chelate two metal ions that are either provided from one IN active site or two active sites juxtaposed together in a higher order tetramer. Herein, we show that all the new compounds are highly potent against purified IN with varied ...

Rational Design and Synthesis of Novel Dimeric Diketoacid-Containing Inhibitors of HIV-1 Integrase: Implication for Binding to Two Metal Ions on the Active Site of Integrase

An essential step in the HIV life cycle is integration of the viral DNA into the host chromosome. This step is catalyzed by a 32-kDa viral enzyme HIV integrase (IN). HIV-1 IN is an important and validated target, and the drugs that selectively inhibit this enzyme, when used in combination with reverse transcriptase (RT) and protease (PR) inhibitors, are believed to be highly effective in suppressing the viral replication. IN catalyzes two discrete enzymatic processes referred to as 3‘ processing and DNA strand transfer. As a part of a study to optimize new lead molecules we previously identified from a series of 2-mercaptobenzenesulfonamides (MBSAs), we applied three-dimensional quantitative structure−activity relationship methods, comparative molecular field analysis (CoMFA), and comparative molecular similarity indices analysis (CoMSIA) to training sets of up to 66 compounds. Two different conformational templates were used:  Conf-d, obtained from docking into the HIV-1 IN active site and Conf-s obtaine...

Application of CoMFA and CoMSIA 3D-QSAR and docking studies in optimization of mercaptobenzenesulfonamides as HIV-1 integrase inhibitors.

Human immunodeficiency virus type 1 integrase (HIV-1 IN) is an essential enzyme for effective viral replication. Therefore, IN inhibitors are being sought for chemotherapy against AIDS. We had previously identified a series of salicylhydrazides as potent inhibitors of IN in vitro (Neamati, N.; et al. J. Med. Chem. 1998, 41, 3202−3209.). Herein, we report the design, synthesis, and antiviral activity of three novel mercaptosalicylhydrazide (MSH) derivatives. MSHs were effective against the IN catalytic core domain and inhibited IN binding to HIV LTR DNA. They also inhibited catalytic activities of IN in IN−DNA preassembled complexes. Site-directed mutagenesis and molecular modeling studies suggest that MSHs bind to cysteine 65 and chelate Mg2+ at the active site of HIV-1 IN. Contrary to salicylhydrazides, the MSHs are 300-fold less cytotoxic and exhibit antiviral activity. They are also active in Mg2+-based assays, while IN inhibition by salicylhydrazides is strictly Mn2+-dependent. Additionally, in target...

Jim A. Turpin

Papers

Metal-dependent inhibition of HIV-1 integrase.