A nonnucleoside reverse transcriptase inhibitor active on human immunodeficiency virus type 1 isolates resistant to related inhibitors (original) (raw)
Related papers
Antimicrobial Agents and Chemotherapy, 1992
The reverse transcriptase (RT) of human immunodeficiency virus type 1 (HIV-1) is potently inhibited by a structurally diverse group of nonnucleoside compounds. These include pyridinone derivatives, tetrahydroimadazo[4,5,1-j,kJ[1,41-benzodiazepin-2(lH)-one and-thione, and BI-RG-587 (nevirapine). The compounds act noncompetitively, by an unknown mechanism, with respect to template-primer and nucleotide substrates. Despite a high degree of similarity between the 1IV-1 and HIV-2 RTs, the HIV-2 enzyme is totally insensitive to these inhibitors. Using a novel method for joining DNA sequences, we have exploited this difference between the two enzymes to identify the regions of the RT that contribute to the compounds' inhibitory activities. The relative in vitro sensitivities of HIV-1/HIV-2 chimeric and site-specific mutant enzymes were determined. Sensitivity to inhibition was largely, though not exclusively, dependent upon the RT region defined by amino acid residues 176 to 190, with specific contributions by residues 181 and 188. The region defined by residues 101 to 106 was found to functionaliy interact with the domain from 155 to 217. In addition, the functional equivalence of the three inhibitor groups was shown. Upon infection of susceptible cells by human immunodeficiency virus type 1 (HIV-1), the viral reverse transcriptase (RT) catalyzes the synthesis of a double-stranded DNA copy of the viral RNA genome. This reverse transcription is essential for viral infectivity, as inhibition of RT blocks viral replication. Thus, this enzyme has been a major focus in anti-HIV drug development and is the target of the nucleoside analogs 3'-azido-2',3'-dideoxythymidine (AZT) and 2',3'-dideoxyinosine (ddI), which are the only currently approved drugs for anti-HIV therapy. These drugs appear to act by mediating premature chain termination of nascent DNA strands (reviewed in reference 17). Neither of these drugs is absolutely HIV specific, and treatment is associated with toxicity that limits their long-term use in the clinic. A separate pharmacologic class of nonnucleoside inhibitors was recently identified and consists of several distinct structural classes of compounds. These are shown in Fig. 1 and include L-697,639, a member of the pyridinone class of inhibitors (7, 23); BI-RG-587 (nevirapine), one of several inhibitory dipyridodiazepinones (16); and R82150 and R82913, tetrahydroimadazo[4,5,1-j,k][1,4]-benzodiazepin-2 (1H)-one and-thione (TIBO) compounds (19). Inhibition of RT activity by these compounds is characteristic of a slowly binding, reversible inhibitor and is noncompetitive with respect to template-primer and nucleotide substrates (6, 7, 16, 29, 30). In contrast to the nucleoside analogs, these compounds are highly specific for HIV-1 RT (RT1), and little or no inhibitory activity is observed against a variety of other viral or cellular polymerases, including the HIV-2 RT (RT2) (6, 7, 16, 29). A major concern in any antiviral drug development effort * Corresponding author.
HIV Therapy, 2009
Since the introduction of the HAART, non-nucleoside reverse transcriptase inhibitors (NNRTIs) have played an essential role in treating HIV: their strong antiviral potency, good metabolic profile and low pill burden make them an ideal option in the design of an optimized triple drug regimen. Nonetheless, the currently approved NNRTIs (efavirenz and nevirapine) are weighed by peculiar toxicities, while a low genetic barrier and the development of cross-resistance significantly limits their use in cases of suboptimal adherence. Many drugs are in development and they are all designed with the aim to overcome resistance problems. In this review we present data on virological efficacy and resistance profiles of some of the most promising new molecules: some (such as rilpivirine) are close to being marketed, others are in Phase II trials (IDX899 and RDEA806), others again have just completed preclinical studies and are having their first clinical evaluations (RO-5028, UK-453061 and BILR-3...
New pyridinone derivatives as potent HIV-1 nonnucleoside reverse transcriptase inhibitors
Journal of medicinal chemistry, 2009
Several 5-ethyl-6-methyl-4-cycloalkyloxy-pyridin-2(1H)-ones were synthesized and evaluated for their anti HIV-1 activities against wild-type virus and clinically relevant mutant strains. A racemic mixture (10) with methyl substituents at positions 3 and 5 of the cyclohexyloxy moiety had potent antiviral activity against wild-type HIV-1. Subsequent stereoselective synthesis of a stereoisomer displaying both methyl groups in equatorial position was found to have the best EC(50). Further modulations focused on position 3 of the pyridinone ring improved the antiviral activity against mutant viral strains. Compounds bearing a 3-ethyl (22) or 3-isopropyl group (23) had the highest activity against wild-type HIV-1 and displayed low-nanomolar potency against several clinically relevant mutant strains.
Antimicrobial Agents and Chemotherapy, 2009
ABSTRACTNonnucleoside reverse transcriptase inhibitors (NNRTIs) have proven efficacy against human immunodeficiency virus type 1 (HIV-1). However, in the setting of incomplete viral suppression, efavirenz and nevirapine select for resistant viruses. The diarylpyrimidine etravirine has demonstrated durable efficacy for patients infected with NNRTI-resistant HIV-1. A screening strategy used to test NNRTI candidates from the same series as etravirine identified TMC278 (rilpivirine). TMC278 is an NNRTI showing subnanomolar 50% effective concentrations (EC50values) against wild-type HIV-1 group M isolates (0.07 to 1.01 nM) and nanomolar EC50values against group O isolates (2.88 to 8.45 nM). Sensitivity to TMC278 was not affected by the presence of most single NNRTI resistance-associated mutations (RAMs), including those at positions 100, 103, 106, 138, 179, 188, 190, 221, 230, and 236. The HIV-1 site-directed mutant with Y181C was sensitive to TMC278, whereas that with K101P or Y181I/V w...
Journal of Medicinal Chemistry, 2005
In the treatment of AIDS, the efficacy of all drugs, including non-nucleoside inhibitors (NNRTIs) of HIV-1 reverse transcriptase (RT), has been limited by the rapid appearance of drug-resistant viruses. Lys103Asn, Tyr181Cys, and Tyr188Leu are some of the most common RT mutations that cause resistance to NNRTIs in the clinic. We report X-ray crystal structures for RT complexed with three different pyridinone derivatives, R157208, R165481, and R221239, at 2.95, 2.9, and 2.43 Å resolution, respectively. All three ligands exhibit nanomolar or subnanomolar inhibitory activity against wild-type RT, but varying activities against drugresistant mutants. R165481 and R221239 differ from most NNRTIs in that binding does not involve significant contacts with Tyr181. These compounds strongly inhibit wild-type HIV-1 RT and drug-resistant variants, including Tyr181Cys and Lys103Asn RT. These properties result in part from an iodine atom on the pyridinone ring of both inhibitors that interacts with the main-chain carbonyl oxygen of Tyr188. An acrylonitrile substituent on R165481 substantially improves the activity of the compound against wild-type RT (and several mutants) and provides a way to generate novel inhibitors that could interact with conserved elements of HIV-1 RT at the polymerase catalytic site. In R221239, there is a flexible linker to a furan ring that permits interactions with Val106, Phe227, and Pro236. These contacts appear to enhance the inhibitory activity of R221239 against the HIV-1 strains that carry the Val106Ala, Tyr188Leu, and Phe227Cys mutations.