Novel Protease Inhibitors (PIs) Containing Macrocyclic Components and 3( R ),3a( S ),6a( R )- bis -Tetrahydrofuranylurethane That Are Potent against Multi-PI-Resistant HIV-1 Variants In Vitro

Abstract

Natural products with macrocyclic structural features often display intriguing biological properties. Molecular design incorporating macrocycles may lead to molecules with unique protein-ligand interactions. We generated novel human immunodeficiency virus type 1 (HIV-1) protease inhibitors (PIs) containing a macrocycle and bis-tetrahydrofuranylurethane.

Novel HIV-1 Protease Inhibitors (PIs) Containing a Bicyclic P2 Functional Moiety, Tetrahydropyrano-Tetrahydrofuran, That Are Potent against Multi-PI-Resistant HIV-1 Variants

“…We have previously designed and synthesized a series of PIs possessing a bis-THF moiety that interacts with the backbone atoms of the catalytic site amino acids, Asp29 and Asp30, of HIV-1 protease (1,19,32). In the present study, we report two newly generated PIs, GRL-1388 and -1398 (Fig.…”

GRL-04810 and GRL-05010, Difluoride-Containing Nonpeptidic HIV-1 Protease Inhibitors (PIs) That Inhibit the Replication of Multi-PI-Resistant HIV-1 In Vitro and Possess Favorable Lipophilicity That May Allow Blood-Brain Barrier Penetration

“…To our knowledge, the suppression failure of APV-resistant variants has largely been seen in all of the bis-THF-containing PIs thus far published (28,(31)(32)(33). The reduced activity of the bis-THF-containing PIs to block the replication of APV-resistant variants is likely due to the structural similarity between the bis-THF-containing PIs, including GRL-04810, GRL-05010, and DRV.…”

A Modified P1 Moiety Enhances In Vitro Antiviral Activity against Various Multidrug-Resistant HIV-1 Variants and In Vitro Central Nervous System Penetration Properties of a Novel Nonpeptidic Protease Inhibitor, GRL-10413

“…Previously reported GRL-labeled PIs (30)(31)(32), including DRV, were generated based on the structure of APV, so they were generally less active against APV-resistant HIV-1 variants. However, GRL-10413 effectively inhibited the replication of HIV-1 APV R 5 M , with an EC 50 of 0.0021 M (6-fold difference from the EC 50 against wild-type HIV-1), indicating that GRL-10413 should have a unique antiviral feature compared to such previously reported GRL-labeled PIs.…”

“…Proviral DNA samples obtained from the lysates of infected cells were subjected to nucleotide sequencing. This drug selection procedure was carried out until the drug concentration reached 5 M, as previously described (29)(30)(31)(32). In the experiments for selection of drug-resistant variants, MT-4 cells were also exploited as target cells, since HIV-1 generally replicates at greater levels in MT-4 cells than in MT-2 cells, as described above.…”