Covalent inhibitors for eradication of drug-resistant HIV-1 reverse transcriptase: From design to protein crystallography

Abstract

Development of resistance remains a major challenge for drugs to treat HIV-1 infections, including those targeting the essential viral polymerase, HIV-1 reverse transcriptase (RT). Resistance associated with the Tyr181Cys mutation in HIV-1 RT has been a key roadblock in the discovery of nonnucleoside RT inhibitors (NNRTIs). It is the principal point mutation that arises from treatment of HIV-infected patients with nevirapine, the first-in-class drug still widely used, especially in developing countries. We report covalent inhibitors of Tyr181Cys RT (CRTIs) that can completely knock out activity of the resistant mutant and of the particularly challenging Lys103Asn/Tyr181Cys variant. Conclusive evidence for the covalent modification of Cys181 is provided from enzyme inhibition kinetics, mass spectrometry, protein crystallography, and antiviral activity in infected human T-cell assays. The CRTIs are also shown to be selective for Cys181 and have lower cytotoxicity than the approved NNRTI drugs efavirenz and rilpivirine.

Structural insights into the recognition of nucleoside reverse transcriptase inhibitors by HIV‐1 reverse transcriptase: First crystal structures with reverse transcriptase and the active triphosphate forms of lamivudine and emtricitabine

“…To date, there are no structural data available for (−)/(+)FTC‐TP and (−)3TC‐TP in complex with RT. The recent success in structure‐based design of novel nonnucleoside reverse transcriptase inhibitors (NNRTIs) with improved pharmacokinetics and less susceptibility toward drug resistance underscore the value of structural data . Similarly, in order to understand the molecular basis of recognition for NRTIs by RT and host Pols important in toxicity, obtaining structural data of RT in complex with (−)FTC‐TP and (−)3TC‐TP is imperative.…”

“…The recent success in structure-based design of novel nonnucleoside reverse transcriptase inhibitors (NNRTIs) with improved pharmacokinetics and less susceptibility toward drug resistance underscore the value of structural data. [17][18][19][20][21][22] Similarly, in order to understand the molecular basis of recognition for NRTIs by RT and host Pols important in toxicity, obtaining structural data of RT in complex with (−) FTC-TP and (−)3TC-TP is imperative. Together with kinetic data, knowledge of the active site architecture for RT with these NRTIs bound is essential for the rational design of new molecules that bind highly selective toward RT.…”

Discovery, synthesis, and optimization of an N-alkoxy indolylacetamide against HIV-1 carrying NNRTI-resistant mutations from the Isatis indigotica root

“…In order to better understand the possible binding mode of the active compounds, the potent 10i and CI -39 as well as the positive controls NVP and EFV were docked into the HIV-1 WT RT (PDB code: 1TL1) [69] and the HIV-1 RT mutants RT-Y181C (PDB code: 1JLB) [70], RT-K103N/Y181C (PDB code: 5VQY) [71], and RT-L100I/ K103N (PDB code: 2ZE2) [72], respectively. The docking results of 10i into WT RT ( Fig.…”

Eine strukturelle Evaluierung medizinalchemischer Strategien gegen Wirkstoffresistenzen

“…[245] Zuvor hatte die Forschungsgruppe eine neue Klasse von 2-Naph-thylcatecholdiether-Derivaten entdeckt, welche die Wildtyp-HIV-1-RTm it nanomolarer Affinitäti nhibieren kçnnen. [245] Zuvor hatte die Forschungsgruppe eine neue Klasse von 2-Naph-thylcatecholdiether-Derivaten entdeckt, welche die Wildtyp-HIV-1-RTm it nanomolarer Affinitäti nhibieren kçnnen.…”

“…[246] Die Analyse der Cokristallstruktur von Inhibitor 48 (Abbildung 37) mit Wildtyp-HIV-1-RT( PDB ID:5 TER, Abbildung 38 A) [246] zeigte,d ass das an die Naphthylgruppe gebundene Chloratom zu Tyr181 orientiert ist, wobei dieser Rest bei wirkstoffresistenten Stämmen zu Cys mutiert. [245] Dafürw urden einige elektrophile Michael-Akzeptoren mit geringer chemischer Reaktivitätz ur Vermeidung von unspezifischen Reaktionen ausgewählt, um das Chloratom zu ersetzen (a-Halogenketone und a-Halogenamide).…”