Dual Inhibitors for Aspartic Proteases HIV-1 PR and Renin: Advancements in AIDS–Hypertension–Diabetes Linkage via Molecular Dynamics, Inhibition Assays, and Binding Free Energy Calculations

Abstract

Human immunodeficiency virus type 1 protease (HIV-1 PR) and renin are primary targets toward AIDS and hypertension therapies, respectively. Molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) free-energy calculations and inhibition assays for canagliflozin, an antidiabetic agent verified its effective binding to both proteins (ΔG(pred) = -9.1 kcal mol(-1) for canagliflozin-renin; K(i,exp)= 628 nM for canagliflozin-HIV-1 PR). Moreover, drugs aliskiren (a renin inhibitor) and darunavir (an HIV-1 PR inhibitor) showed high affinity for HIV-1 PR (K(i,exp)= 76.5 nM) and renin (K(i,pred)= 261 nM), respectively. Importantly, a high correlation was observed between experimental and predicted binding energies (r(2) = 0.92). This study suggests that canagliflozin, aliskiren, and darunavir may induce profound effects toward dual HIV-1 PR and renin inhibition. Since patients on highly active antiretroviral therapy (HAART) have a high risk of developing hypertension and diabetes, aliskiren-based or canagliflozin-based drug design against HIV-1 PR may eliminate these side-effects and also facilitate AIDS therapy.

Dynamic and Electrostatic Effects on the Reaction Catalyzed by HIV-1 Protease

“…2 HIV-1 PR is an enzyme of the aspartic proteases family which is characterized by the presence of two eponymous aspartyl residues in the active site located at the bottom of a substrate-binding cleft. 3, 4, 5, 6, 7, 8, 9 The structure of the HIV-1 PR, together with a detail of the active site with the substrate and the mentioned water molecule is presented on Figure 1.…”

Identification of putative biomarkers for HIV-associated neurocognitive impairment in the CSF of HIV-infected patients under cART therapy determined by mass spectrometry

“…Renin receptor levels were also increased in the CSF of HAND individuals. While renin has been connected to HIV nephropathy and the renin-angiotensin system is impacted by cART (Tzoupis et al 2012), no connections yet have been made to HIV neurological disease. Genetic defects in renin receptor are linked to profound mental retardation.…”

Renin modulates HIV replication in T cells

“…In addition, serum Ang I levels have been reported to display the bioavailability of protease inhibitors [28,29]. It has been speculated that protease inhibitors also attenuate high blood pressure in HIV patients [30]. It has been speculated that protease inhibitors also attenuate high blood pressure in HIV patients [30].…”

“…Our findings are consistent with those reports. It has been speculated that protease inhibitors also attenuate high blood pressure in HIV patients [30]. However, the role of (P)RR-and renin-mediated proteolytic activity in HIV replication has not been studied.…”