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An Amphiphilic Conjugate Approach toward the Design and Synthesis of Betulinic Acid–Polyphenol Conjugates as Inhibitors of the HIV-1 gp41 Fusion Core Formation

Yan Liu,Zhuofeng Ke,Kwok Yiu Wu,Shuwen Liu,Wen-Hua Chen,Shibo Jiang,Zhi-Hong Jiang

Graphical Stopping HIV in its tracks! A series of betulinic acid–polyphenol conjugates were synthesized, with the aid of rational design by docking simulation, as novel HIV-1 fusion/entry inhibitors targeting gp41. These amphiphilic conjugates cooperatively interact with hydrophobic and hydrogen-bonding areas in the groove of the gp41 NHR trimeric coiled coil, demonstrating a promising strategy for the discovery of HIV-1 fusion/entry inhibitor binding to these two crucial pockets. Exploration of potent inhibitors of the HIV-1 gp41 fusion core formation is a promising strategy to discover small-molecule HIV-1 entry inhibitors for the treatment of HIV-1 infection. In this paper, a series of novel betulinic acid–polyphenol conjugates was designed, guided by molecular modeling of the binding of betulinic acid (BA) and phenolic galloyl/caffeoyl groups in the groove on the gp41 N-terminal heptad repeat (NHR) trimeric coiled coil. These conjugates were synthesized via conjugation of galloyl and caffeoyl groups with BA at the C-28 position. Their inhibitory activities of HIV gp41 six-helix bundle (6-HB) formation between the NHR peptide N36 and the C-terminal heptad repeat (CHR) peptide C34 were evaluated with size-exclusion HPLC. Conjugates bearing a galloyl group were found to exhibit four to sixfold higher inhibitory activities than that of parent compound BA, suggesting that they may be exploitable as HIV-1 fusion/entry inhibitors targeting gp41. The docking study on BA and its derivatives suggests that hydrophobic and hydrogen-bonding pockets exist in the groove of the gp41 NHR trimeric coiled coil and that a potent inhibitor should have amphiphilic structures to cooperatively interact with both pockets. This possibility was explored by incorporating both lipophilic and hydrophilic groups into the conjugates in a well-defined orientation to bind with both pockets in the gp41 NHR-trimer.