Potent Inhibitors Active against HIV Reverse Transcriptase with K101P, a Mutation Conferring Rilpivirine Resistance

Abstract

Catechol diether compounds have nanomolar antiviral and enzymatic activity against HIV with reverse transcriptase (RT) variants containing K101P, a mutation that confers high-level resistance to FDA-approved non-nucleoside inhibitors efavirenz and rilpivirine. Kinetic data suggests that RT (K101P) variants are as catalytically fit as wild-type and thus can potentially increase in the viral population as more antiviral regimens include efavirenz or rilpivirine. Comparison of wild-type structures and a new crystal structure of RT (K101P) in complex with a leading compound confirms that the K101P mutation is not a liability for the catechol diethers while suggesting that key interactions are lost with efavirenz and rilpivirine.

Computer-aided discovery of anti-HIV agents

“…72 The results are clearly striking, especially for 27 , which shows the greatest potency among the four NNRTIs for all viral strains, no cytotoxicity towards T-cells, and good solubility. Both 21 and 27 show excellent activity towards the WT and Y181C—containing strains with no loss of potency for the K101P variant.…”

“…After addition of the test compounds and infection with viral strains, the cells are incubated for three days at 37 °C, and then the extent of infectivity is quantified by flow cytometry. 72 The evaluations were carried out with several HIV-1 strains including WT and ones bearing the Y181C, K103N, and K101P mutations in RT. We were particularly interested in the latter mutation as multiple variations of Lys101 (K101E, K101H, K101P) are known to cause resistance to all FDA-approved NNRTIs.…”

“…Crystal structures were also compared for efavirenz, rilpivirine, and 27 with WT RT, and a new structure for 27 with K101P RT was reported. 72 Since the catechol diethers do not have the hydrogen bond with the backbone carbonyl of Lys101 that is characteristic of almost all NNRTIs including 2 (Fig. 2), efavirenz, and the TMC compounds, the catechol diethers are positioned farther back in the NNRTI binding site and do not contact residue 101.…”

Structural and Preclinical Studies of Computationally Designed Non-Nucleoside Reverse Transcriptase Inhibitors for Treating HIV infection

“…Additional free-energy perturbation-guided efforts then addressed possible replacements of the cyanovinylphenyl substructure, which led to discovery of additional novel compounds, including compound II (Bollini et al, 2011;Lee et al, 2014). These compounds are highly effective NNRTIs that have strong potential for development as new anti-HIV-1 drugs with improved antiviral efficacy and drug resistance profiles (Lee et al, 2013(Lee et al, , 2014Frey et al, 2014Frey et al, , 2015Gray et al, 2015). As noted in Table 1, these compounds are suitable drug candidates for further preclinical studies due to their low effective intrinsic inhibitory activities at low nanomolar concentrations, better solubility profiles, and low C log P values compared with rilpivirine (Janssen et al, 2005;Sun et al, 2012) and efavirenz (Lee et al, 2013(Lee et al, , 2014Frey et al, 2014).…”

“…Inhibition assays were carried out with the PicoGreen Enzcheck Reverse Transcriptase Assay Kit (Life Technologies, Eugene, OR) as described previously (Gray et al, 2015). The compound solubility was measured using a shake-flask procedure as described previously Lee et al, 2013) Anti-HIV Activity in Infected TZM-bl Cells.…”