Evaluation of novel protease inhibitors against darunavir‐resistant variants of HIV type 1

Abstract

HIV disease became a manageable chronic disease since combination antiretroviral therapy (cART) was introduced as the standard treatment regimen. However, the emergence of drug‐resistant viruses is a major problem associated with cART. A phenotypic drug susceptibility test using a lentiviral vector was established and applied to evaluate new protease inhibitors (PIs). Lentiviral vectors representing a wild‐type (WT‐lentivector) and darunavir (DRV)‐resistant HIV type 1 (HIV‐1) (DRVr‐lentivector) were generated. Nine clinically approved protease inhibitors (PIs) inhibited the transduction ability of WT‐lentivector similar to their inhibitory effects on the replication of WT HIV‐1. Three new PIs reduced the transduction ability of WT‐ and DRVr‐lentivector, suggesting that these PIs may be the candidates as novel antiretroviral drugs against drug‐resistant variants of HIV‐1.

Identification of Highly Potent Human Immunodeficiency Virus Type-1 Protease Inhibitors against Lopinavir and Darunavir Resistant Viruses from Allophenylnorstatine-Based Peptidomimetics with P2 Tetrahydrofuranylglycine

“… a WT: pCMVdR8.91. EC 50 values of SQV, RTV, IDV, NFV, APV, LPV, ATV, and TPV were 1.87, 10.39, 7.17, 17.52, 7.91, 1.60, 0.80, and 82.84, respectively b FR: fold-resistance, the ratio of EC 50 (resistant mutant)/EC 50 (wild-type). …”

“… a WT: pCMVdR8.91. EC 50 values of SQV, RTV, IDV, NFV, APV, LPV, ATV, and TPV were 1.87, 10.39, 7.17, 17.52, 7.91, 1.60, 0.80, and 82.84, respectively …”

“…To further examine the potency of 21f, we prepared twotypes of darunavir-resistant viral assays based on a lentivirus vector infection with 293T cells. 30 The mutation sites in the protease region were derived from an original report by Koh et al 12 First, we tested darunavir, which showed a strong inhibition against wild-type with an EC 50 value of 0.9 nM (Table 6). The potency was attenuated to the virus containing V32I/L33F/I54M/V82I mutations approximately 15-fold.…”

Multiple Molecular Dynamics Simulations and Free-Energy Predictions Uncover the Susceptibility of Variants of HIV-1 Protease against Inhibitors Darunavir and KNI-1657

“…Among the HIV-1 PR drugs available, darunavir (DRV) is the most effective drug against many clinical isolates. − However, the work of Hidaka et al. proved that two derivatives containing V32I/L33F/I54M/V82I and V32I/L33F/I54M/I84V mutations (Figure ) obviously weaken the inhibiting efficiency of several drugs, including DRV with HIV-1 PR. , Recently, a new inhibitor, KNI-1657 (KNI), has been developed, and this inhibitor showed good results in inhibiting the PR activity of DRV-resistant clinical isolates V32I/L33F/I54M/V82I and V32I/L33F/I54M/I84 V derivatives . Among these mutated residues, there is only one residue (V82I or I84 V) in the inhibitor/substrate binding cavity; all other residues are located far from the active site.…”

Synthesis of Biuret Derivatives as Potential HIV‐1 Protease Inhibitors Using (LDHs‐g‐HMDI‐Citric Acid), as a Green Recyclable Catalyst

“…Over time, damages to the immune system by HIV infection lead to different pathological problems, including severe infections and certain cancers 3 . HIV‐1 protease is an enzyme that is crucial for viral assembly and maturation 4 . Viral RNA is translated into a polypeptide sequence that includes several individual proteins (reverse transcriptase, transcriptase, protease, and integrase).…”