Synthesis and biological evaluation of a new derivative of bevirimat that targets the Gag CA-SP1 cleavage site

Bevirimat (2), the first-in-class HIV-1 maturation inhibitor, shows a low efficacy due essentially to the natural polymorphism of its target, the CA-SP1 junction. Moreover, its low hydrosolubility makes it difficult to study its interaction with the CA-SP1 junction. We have synthesized new derivatives of bevirimat by adding different hydrophilic substituents at the C-28 position to improve their hydrosolubility and perform the structural study of a complex by NMR. Synthesis of the new derivatives, the effect of substituents at the C-28 position and their hydrosolubility are discussed. The ability of these molecules to inhibit viral infection and their cytotoxicity is assessed. Compared to the well-known bevirimat (2), one of our compounds (16) shows a higher hydrosolubility associated with a 2.5 fold increase in activity, a higher selectivity index and a better antiviral profile. Moreover, for the first time a direct interaction between a derivative of bevirimat (16) and the domain CA-SP1–NC is shown by NMR. Information from this study should allow us to decipher the mechanism by which bevirimat inhibits HIV-1 maturation and how the natural polymorphism of the spacer peptide SP1 triggers resistance to inhibitors.

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► New bevirimat derivatives were synthesized by addition of substituents at C-28 position.
► New products were tested for their biological activity and their cytotoxicity.
► One of our compounds shows a better antiviral profile that the bevirimat.
► NMR shows a direct interaction between one of our compounds and CA-SP1–NC.
► We aim to decipher the mechanism by which bevirimat inhibits HIV-1 maturation.