New betulinic acid derivatives for bevirimat-resistant human immunodeficiency virus type-1

Abstract

Bevirimat (1, BVM) is an anti-HIV agent that blocks HIV-1 replication by interfering with HIV-1 Gag-SP1 processing at a late stage of viral maturation. However, clinical trials of 1 have revealed a high baseline drug resistance that is attributed to naturally occurring polymorphisms in HIV-1 Gag. To overcome the drug resistance, 28 new derivatives of 1 were synthesized and tested against compound 1-resistant (BVM-R) HIV-1 variants. Among them, compound 6 exhibited much improved activity against several HIV-1 strains carrying BVM-R polymorphisms. Compound 6 was at least 20-fold more potent than 1 against the replication of NL4-3/V370A, which carries the most prevalent clinical BVM-R polymorphism in HIV-1 Gag-SP1. Thus, compound 6 merits further development as a potential anti-AIDS clinical trial candidate.

Figure 1

Structure of compound 1 analogs.

Figure 2

Inhibition of CA-SP1 processing. The anti-maturation activity of 1 and 6 was determined by transfecting 293T cells with the following plasmids: (a) pNL4-3 or pNL4-3/V370A; (b) pNL4-3/V362I. The viruses produced in the presence of the compounds were collected two days after transfection.

Figure 3

Compound 6 did not inhibit HIV-1 Env–mediated cell-cell fusion. COS cells (1 × 10⁶ cells/mL) were transfected by electroporation with HIV-1 NL4-3 Env-expressing vector (2 μg) for one day before mixing with TZM-bl cells for fusion. The luciferase expression measured as relative luciferase units (RLU) in the fusion cells was quantified 24 hours after cell mixing. HIV-1 Env-mediated cell-cell fusion in the absence of compounds is defined as 100% control. Each data point in the figure represents mean +/- SD of three tests.

Scheme 1

Synthesis of Compounds 2-18^a

Scheme 2

Synthesis of Compounds 19-29^a