Unique features in the structure of the complex between HIV-1 reverse transcriptase and the bis(heteroaryl)piperazine (BHAP) U-90152 explain resistance mutations for this nonnucleoside inhibitor

Abstract

The The reverse transcriptase (RT; EC 2.7.7.49) of human immunodeficiency virus (HIV) is a multifunctional enzyme critical to the viral life cycle. It is also without a homologue in eukaryotic systems, and thus is an attractive target for anti-HIV therapies. Several RT inhibitors that act as DNA chainterminating analogues of the natural nucleosides have been used to control HIV infection, such as AZT, ddI, ddC, d4T and 3TC (1). However, the emergence of resistant virus populations and significant adverse reactions (2, 3) led to extensive efforts to identify new RT inhibitors.The search for novel RT inhibitors rapidly identified the nonnucleoside inhibitors (NNIs), compounds that are typically HIV-1 specific. The NNIs now comprise a very large number of chemically diverse (but largely hydrophobic) compounds, which are subdivided into groups based on their chemical structures. From early examples {e.g., 1-(2-hydroxyethoxymethyl-6-(phenylthio)thymine (HEPT) (4), tetrahydroimidazo-[4,5,l-jk][1,4]-benzodiazepin-2(1H)-one (TIBO) (5), and nevirapine (6)} to the recent example of alkenyldiarylmethanes (7), more than 30 groups of NNIs have been identified (8). These compounds can be very potent inhibitors of RT, with low toxicity and favorable pharmacokinetic properties. However, the emergence of resistant viral populations, often within days or weeks, seriously compromises their potential therapeutic efficacy. Resistance studies suggest that the NNIs share a common mode of action, binding at a single site that is distinct from the polymerase catalytic site (8). Mutations that confer resistance to one NNI often confer cross-resistance to many other inhibitors [such as the Lys-103-Asn and Tyr-181-Cys mutations (9-11)] and so interest has focused on those compounds that retain pronounced activity against mutant RTs or that have a unique resistance profile.The first structure determination for RT [in complex with the NNI nevirapine at 3.5-Å resolution (12)] has been followed by structures of complexes with other NNIs (13-17), a complex with double-stranded DNA (18), and structures of the unliganded . The structures we have determined to 2.2-Å resolution for RT in complex with NNIs (13) represent the clearest models of RT to date; hence, we use the secondary structure nomenclature of these descriptions. RT is a heterodimer, one subunit (p66) comprises 560 residues and all enzymatic activity of the heterodimer is associated with residues in this subunit. The second chain (p51) comprises the initial 440 residues of the p66 subunit. RT is composed of nine domains (12), named fingers, palm, thumb, connection, and RNase H in the p66, with the p51 containing only the first four of these. The domains of the p66 subunit form a binding groove for the polynucleotide substrate, at the bottom of which lie the aspartyl residues implicated in polymerase activity.The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked ''advertisement'' in accordance with 18 U....

A proline-to-histidine substitution at position 225 of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) sensitizes HIV-1 RT to BHAP U-90152.

“…The greater sensitivity of the P225H recombinant mutant virus and P225H recombinant mutant RT to BHAP U-90152 is in full agreement with the structure of the RT-BHAP complex determined by X-ray crystallography (Fig. 1 D ; Esnouf et al, 1997). When BHAP U-90152 binds to HIV-1 RT, the methylsulphonamide moiety protrudes into the solvent creating a channel between P236 and the polypeptide segments 225-226 and 105-106.…”

“…It gave moderate resistance to most NNRTIs, but remarkable sensitivity to one particular NNRTI (BHAP U-90152). We have been able to offer a molecular explanation for this phenomenon (Pelemans et al, 1997 ;Esnouf et al, 1997 ; and this study) based on crystallographic and modelling studies of the NNRTIs in complex with HIV-1 RT.…”

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“…The key interactions involved in binding are summarised in Table 18 with reference to ligand 1klm and Table 17 shows the features present in each ligand [38][39][40][41][42][43][44][45][46][47]. The only feature which is common to all ligands is the hydrophobe H and this thus represents the target pharmacophore.…”

Regiospecific Synthesis and Anti-Human Immunodeficiency Virus Activity of Novel 5-Substituted N-Alkylcarbamoyl and N,N-Dialkyl Carbamoyl 1,2,3-Triazole-TSAO Analogues

“…Subsequent molecular modelling studies suggested a binding orientation for the triazole ring compatible with these binding differences and provided new ideas for further structural modifications. The 1,2,3-triazole-TSAO series of compounds reported herein was conceived on the premise of an additional hydrophobic interaction in a region of the NNRTI binding site that has actually been explored for other known inhibitors (Esnouf et al, 1997). Our reported procedure for the synthesis of the carbamoyl substituted-1,2,3-triazole-TSAO analogues (Alvarez et al, 1994) gave the most active 5-isomers as minor products in low yields.…”