title: An amphiphilic conjugate approach toward the design and synthesis of betulinic acid-polyphenol conjugates as inhibitors of the HIV-1 gp41 fusion core formation.
abstract: 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.
authors.affiliation: School of Chinese Medicine, Hong Kong Baptist University, 7 Baptist University Road, Kowloon Tong, Kowloon, Hong Kong, P.R. China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Liu
authors.forename: Zhuofeng
authors.initials: Z
authors.lastname: Ke
authors.forename: Kwok Yiu
authors.initials: KY
authors.lastname: Wu
authors.forename: Shuwen
authors.initials: S
authors.lastname: Liu
authors.forename: Wen-Hua
authors.initials: WH
authors.lastname: Chen
authors.forename: Shibo
authors.initials: S
authors.lastname: Jiang
authors.forename: Zhi-Hong
authors.initials: ZH
authors.lastname: Jiang
mesh_terms: D000465:Algorithms; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D015700:HIV Envelope Protein gp41 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D023581:HIV Fusion Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D015658:HIV Infections / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D006860:Hydrogen Bonding; D057927:Hydrophobic and Hydrophilic Interactions; D008958:Models, Molecular; D053978:Pentacyclic Triterpenes; D059808:Polyphenols / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D014315:Triterpenes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000094062:Betulinic Acid
chemical_list: D015700:HIV Envelope Protein gp41; D023581:HIV Fusion Inhibitors; D053978:Pentacyclic Triterpenes; D059808:Polyphenols; D014315:Triterpenes; D000094062:Betulinic Acid