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

Abstract

We have determined the crystal structure of the HIV type 1 reverse transcriptase complexed with CP-94,707, a new nonnucleoside reverse transcriptase inhibitor (NNRTI), to 2.8-Å resolution. In addition to inhibiting the wild-type enzyme, this compound inhibits mutant enzymes that are resistant to inhibition by nevirapine, efavirenz, and delaviridine. In contrast to other NNRTI complexes where tyrosines 181 and 188 are pointing toward the enzyme active site, the binding pocket in this complex has the tyrosines pointing the opposite direction, as in the unliganded protein structure, to accommodate CP-94,707. This conformation of the pocket has not been observed previously in NNRTI complexes and substantially alters the shape and surface features that are available for interactions with the inhibitor. One ring of CP-94,707 makes extensive stacking interactions with tryptophan 229, one of the few residues in the NNRTI-binding pocket that cannot readily mutate to give rise to drug resistance. In this conformation of the pocket, mutations of tyrosines 181 and 188 are less likely to disrupt inhibitor binding. Modeling the asparagine mutation of lysine 103 shows that a hydrogen bond between it and tyrosine 188 could form as readily in the CP-94,707 complex as it does in the apoenzyme structure, providing an explanation for the activity of this inhibitor against this clinically important mutant.

A Direct, Regioselective Palladium‐Catalyzed Synthesis of N‐Substituted Benzimidazoles and Imidazopyridines

“…[1] The ability of this heterocyclic scaffold to solicit an interaction with a variety of biological targets is well documented by the multitude of reports on the observed biological activity, as well as by the fact that several benzimidazole-based compounds are in development or marketed as drugs. [2][3][4][5][6][7] In many cases, the benzimidazole is unsymmetrically substituted at one of the nitrogen atoms of the imidazole moiety. In spite of the great importance of this scaffold, only a very few general regioselective routes to N-substituted benzimidazoles have been reported so far.…”

HIV-1 Reverse Transcriptase Structure with RNase H Inhibitor Dihydroxy Benzoyl Naphthyl Hydrazone Bound at a Novel Site

“…A recently published structure for RT in a complex with the NNRTI CP-94,707 (27) suggests the idea that there is an opportunity to develop DHBNH derivatives that have NNRTI-like activity. The RT/CP-94,707 structure is similar to the RT/DHBNH structure in that the side chains of Tyr181 and Tyr188 are in the conformation seen in unliganded RT, and the overall conformations of the polymerase active site and NNRTI-binding pocket are very similar to those of RT/DHBNH ( Figure 5).…”

Novel Nonnucleoside Inhibitors That Select Nucleoside Inhibitor Resistance Mutations in Human Immunodeficiency Virus Type 1 Reverse Transcriptase

“…Mutations such as M184V, L74V, K65R, and thymidine analogue mutations, including M41L, D67N, K70R, L210W, T215Y/F, and K219Q, are responsible for resistance to the currently approved NRTIs. NNRTIs bind to a unique hydrophobic pocket located near the palm subdomain of HIV-1 RT, which interferes with cooperative movements between the finger and thumb subdomains, thereby inhibiting catalysis of the enzyme (16,19,22,26). The predominant RT mutations in viruses isolated from NNRTItreated patients are K103N and Y181C.…”