Design and synthesis of highly potent HIV-1 protease inhibitors with novel isosorbide-derived P2 ligands

Recent Progress in the Development of HIV-1 Protease Inhibitors for the Treatment of HIV/AIDS

“…Inhibitor 24 , with a methoxy substituent, showed an IC 50 value of 0.05 nM. 93 When docked in the X-ray crystal structure of wild-type HIV-1 protease, it was found that inhibitor 24 maintained a similar binding mode as darunavir. The top ring oxygen of the isosorbide P2 ligand formed hydrogen bonds with the amide NHs of Asp29 and Asp30, similar to the bis-THF moiety of darunavir.…”

“…The C6 methoxy group did not make any polar interactions in the active site according to the docking model. 93 …”

Highly Resistant HIV-1 Proteases and Strategies for Their Inhibition

“…Qiu et al [64] synthesized DRV-based inhibitors that replaced the bis-THF at P2 with an isosorbide trans-4-hydroxy-L-prolinamide. The isosorbide inhibitors demonstrated a two orders of magnitude improvement in antiviral activity against wild type HIV in comparison to IDV, however, no comparison was reported with DRV and the experimental structure is unknown.…”

Exploration of the structural requirements of HIV-protease inhibitors using pharmacophore, virtual screening and molecular docking approaches for lead identification

“…However owing to the rapid emergence of drug-resistant HIV-1 variants and transmission of these resistant viral strains along with the adverse side effects of currently used HIV-1 PIs, are remain critical factors that limiting the clinical effectiveness of HAART [13][14][15]. Numerous groups worldwide have developed HIV-1 protease inhibitors, showing excellent antiviral profiles [16][17][18][19][20][21][22]. Up to now, some clinically approved HIV-1 protease inhibitors including atazanavir, indivanir, nelfinavir and sequinavir are available in the market for HIV treatment but they are very peptide-like and have poor bio-availability.…”