Structural and pharmacological evaluation of a novel non-nucleoside reverse transcriptase inhibitor as a promising long acting nanoformulation for treating HIV

Abstract

Combination antiretroviral therapy (cART) has been proven effective in inhibiting human immunodeficiency virus type 1 (HIV-1) infection and has significantly improved the health outcomes in acquired immune deficiency syndrome (AIDS) patients. The therapeutic benefits of cART have been challenged because of the toxicity and emergence of drug-resistant HIV-1 strains along with lifelong patient compliance resulting in non-adherence. These issues also hinder the clinical benefits of non-nucleoside reverse transcriptase inhibitors (NNRTIs), which are one of the vital components of cART for the treatment of HIV-1 infection. In this study, using a computational and structural based drug design approach, we have discovered an effective HIV-1 NNRTI, compound I (Cmpd I) that is very potent in biochemical assays and which targets key residues in the allosteric binding pocket of wild-type (WT)-RT as revealed by structural studies. Furthermore, Cmpd I exhibited very potent antiviral activity in HIV-1 infected T cells, lacked cytotoxicity (therapeutic index >100,000), and no significant off-target effects were noted in pharmacological assays. To address the issue of non-adherence, we developed a long-acting nanoformulation of Cmpd I (Cmpd I-NP) using poly(lactide-coglycolide) (PLGA) particles. The

Structural investigation of 2‐naphthyl phenyl ether inhibitors bound to WT and Y181C reverse transcriptase highlights key features of the NNRTI binding site

“…In comparison, Compound 2 interacts much more strongly with W229 (Figure 5b) and only shows a 10‐fold reduction against the mutant strain. Furthermore, a compound from the 1‐naphthyl class of catechol diethers, which has been shown to make an even more extended edge to face interaction with W229 than that observed for Compound 2 (Figure 5c), 22 displays only a threefold reduction in activity against Y181C HIV 23 . This comparison suggests that the more a compound interacts with W229 within the NNRTI binding site, the more likely it will have the ability to overcome the Y181C resistance mutation in HIV.…”

“… 20 The nearly identical bound conformations of 2 , 3 , and 4 most likely result from the shared methyl group substitution at the 1‐position of the naphthyl ring, which severely restricts the conformational freedom of the 2‐naphthyl compounds 20 . The increased activity measured for 4 may result from the addition of the fluorine on the catechol ring as seen in other classes of catechol diether inhibitors 22,23 …”

Nanotechnology for virus treatment

“…Other examples of nanodelivery platforms for HIV treatment include solid lipid nanoparticles (SLNs) loaded with the protease inhibitor ritonavir [ 103 ] and hydrophobic core graft copolymer loaded with the NNRTI enzophenone-uracil [ 104 ]. Polymeric nanoparticles, particularly those composed of poly(lactic- co -glycolic acid) (PLGA), are an attractive platform for drug delivery largely due to their biodegradable and biocompatible properties [ [105] , [106] , [107] , [108] ]. Combination therapeutic approaches utilizing nanodelivery have also been widely reported [ [109] , [110] , [111] , [112] , [113] ].…”

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.…”