Phenylethylthiazolylthiourea (PETT) Non-nucleoside Inhibitors of HIV-1 and HIV-2 Reverse Transcriptases

Abstract

A series of biaryl acids has been reported that inhibit both HIV-1 and HIV-2 RT, although these appear not to bind at the NNRTI site (4). NNRTIs such as nevirapine generally act as noncompetitive inhibitors of HIV-1 RT with respect to substrates (5), binding in a pocket some 10 Å from the polymerase active site (6 -8). The NNRTI binding site is contained largely within the p66 subunit of the RT heterodimer with only a few residues at the periphery of the site being contributed by the p51 subunit. The mechanism of inhibition for NNRTIs has been shown to be via a distortion of the key catalytic active site aspartyl residues (9). One series of NNRTIs previously described is the phenylethylthiazoylthiourea (PETT) series that have been shown to have potent activity against both HIV-1 virus and it's RT (10 -13). Further PETT analogues have been designed using information from the three-dimensional structure of HIV-1 RT (14 -16). In this work we report structural and biochemical studies for two members of this series referred to as PETT-1 and PETT-2 (Scheme 1).Most NNRTIs rapidly select for drug-resistant HIV-1 strains, both in tissue culture and in clinical studies, which has largely precluded their use as monotherapy (17). In contrast to the "first-generation" drugs, nevirapine and delavirdine, the so-called "second-generation" NNRTI drug, efavirenz, demonstrates resilience to the effects of certain common resistance mutations (18). However resistance to such compounds is * This work was supported by the European Commission (Project PL96-2161). The Oxford Centre for Molecular Sciences is supported by the Biotechnology and Biological Sciences Research Council, Medical Research Council, and Engineering and Physical Sciences Research Council. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.The atomic coordinates and structure factors (codes 1dtq and 1dtqsf and 1dtt and 1dttsf)

Binding of the Second Generation Non-nucleoside Inhibitor S-1153 to HIV-1 Reverse Transcriptase Involves Extensive Main Chain Hydrogen Bonding

“…Previous crystallographic studies have shown a common binding site for many classes of NNRTI, with a high degree of overlap for chemically divergent compounds (11)(12)(13)(14)(15)(16)(17)(18). Crystallographic and kinetic studies indicate the mechanism of inhibition of NNRTIs is via a distortion of the catalytic aspartate residues in the polymerase active site (19,20).…”

Structure of HIV-1 reverse transcriptase bound to an inhibitor active against mutant reverse transcriptases resistant to other nonnucleoside inhibitors

“…Subsequent structures of the enzyme with a number of different NNRTIs bound have demonstrated that these inhibitors bind to the same pocket, with only minor differences in protein conformation, and substantially overlap the site occupied by nevirapine (6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20). Comparison of these structures with those of the apoenzyme shows that the NNRTI-binding pocket is induced upon NNRTI binding (21)(22)(23)(24).…”

Crystal structure of (E)-(2-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methylene)- N-phenylhydrazinecarbothioamide, C16H15N3O2S

“…Thiourea derivatives have been identified as Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs) [1][2][3][4][5]. There is an increasing concern on thioureas as someo ft hem also have been reported as antiviral [6][7][8], antibacterial [9] and anti-HIV agents [10].W ith the aim of obtaining new antibacterial compounds, (E)-(2-((2,3-dihydrobenzo[b] [1,4]dioxin-6-yl)methylene)-Nphenylhydrazinecarbothioamide was synthesized to study its crystal structure.…”

“…There is an increasing concern on thioureas as someo ft hem also have been reported as antiviral [6][7][8], antibacterial [9] and anti-HIV agents [10].W ith the aim of obtaining new antibacterial compounds, (E)-(2-((2,3-dihydrobenzo[b] [1,4]dioxin-6-yl)methylene)-Nphenylhydrazinecarbothioamide was synthesized to study its crystal structure. Two intermolecular N-H×××Sh ydrogen bond (N×××S1: 3.413(2) Å, N2-H2×××S1: 151°) and an intramolecular N-H×××Nh ydrogen bond (N1×××N3: 2.595(3) Å, N1-H1×××N3: 110°) form in the molecule.Intotal, all bond lengths in the molecules are withinnormalvalues [11].…”