Abstract
We report that GRL-09510, a novel HIV-1 protease inhibitor (PI) containing a newly-generated P2-crown-tetrahydrofuranylurethane (Crwn-THF), a P2′-methoxybenzene, and a sulfonamide isostere, is highly active against laboratory and primary clinical HIV-1 isolates (EC50: 0.0014–0.0028 μM) with minimal cytotoxicity (CC50: 39.0 μM). Similarly, GRL-09510 efficiently blocked the replication of HIV-1NL4-3 variants, which were capable of propagating at high-concentrations of atazanavir, lopinavir, and amprenavir (APV). GRL-09510 was also potent against multi-drug-resistant clinical HIV-1 variants and HIV-2ROD. Under the selection condition, where HIV-1NL4-3 rapidly acquired significant resistance to APV, an integrase inhibitor raltegravir, and a GRL-09510 congener (GRL-09610), no variants highly resistant against GRL-09510 emerged over long-term in vitro passage of the virus. Crystallographic analysis demonstrated that the Crwn-THF moiety of GRL-09510 forms strong hydrogen-bond-interactions with HIV-1 protease (PR) active-site amino acids and is bulkier with a larger contact surface, making greater van der Waals contacts with PR than the bis-THF moiety of darunavir. The present data demonstrate that GRL-09510 has favorable features for treating patients infected with wild-type and/or multi-drug-resistant HIV-1 variants, that the newly generated P2-Crwn-THF moiety confers highly desirable anti-HIV-1 potency. The use of the novel Crwn-THF moiety sheds lights in the design of novel PIs.
Highlights
We report that GRL-09510, a novel human immunodeficiency virus type-1 (HIV-1) protease inhibitor (PI) containing a newly-generated P2crown-tetrahydrofuranylurethane (Crwn-THF), a P2′-methoxybenzene, and a sulfonamide isostere, is highly active against laboratory and primary clinical HIV-1 isolates (EC50: 0.0014–0.0028 μM) with minimal cytotoxicity (CC50: 39.0 μM)
We examined GRL-09510 against an array of HIV-1NL4-3 variants, which had been selected by propagating HIV-1NL4-3 as a starting strain, in the presence of increasing concentrations of each of 3 Food and Drug Administration (FDA)-approved PIs (ATV, LPV and APV) in MT-4 cells[20,21]
We have previously demonstrated a few prototypic PIs (Supplemental Fig. 2) that were highly potent against two wild-type HIV-1s (HIV-1NL4-3 and HIV-1WT/ERS104pre) and a multi-drug resistant clinical strain (HIV1MDR/G)(Supplemental Table 4) with EC50 values ranging from 0.5 to 20 nM
Summary
We report that GRL-09510, a novel HIV-1 protease inhibitor (PI) containing a newly-generated P2crown-tetrahydrofuranylurethane (Crwn-THF), a P2′-methoxybenzene, and a sulfonamide isostere, is highly active against laboratory and primary clinical HIV-1 isolates (EC50: 0.0014–0.0028 μM) with minimal cytotoxicity (CC50: 39.0 μM). The present data demonstrate that GRL-09510 has favorable features for treating patients infected with wild-type and/or multi-drugresistant HIV-1 variants, that the newly generated P2-Crwn-THF moiety confers highly desirable antiHIV-1 potency. We found that GRL-09510 exerts strong activity against a wide spectrum of laboratory HIV-1 strains, an HIV-2 strain, and primary clinical isolates including highly-multi-drug-resistant HIV-1 variants with minimal cytotoxicity. We carried out the selection experiments of GRL-09510-resistant HIV-1 variants by propagating a laboratory wild-type HIV-1NL4-3 strain in the presence of increasing concentrations of the compound, and determined the amino acids substitutions that emerged under the pressure of GRL-09510 in the PR or Gag-encoding region. Performed crystallographic analyses to determine how GRL09510 interacts with the active-site amino acids of PR
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