Dimeric C34 Derivatives Linked through Disulfide Bridges as New HIV‐1 Fusion Inhibitors

• Published in: Chembiochem : a European journal of chemical biology 2019-08, Vol.20 (16), p.2101-2108
• Main Authors: Kobayakawa, Takuya, Ebihara, Kento, Honda, Yuzuna, Fujino, Masayuki, Nomura, Wataru, Yamamoto, Naoki, Murakami, Tsutomu, Tamamura, Hirokazu
• Format: Article
• Language: English
• Subjects: antiviral agents; C-terminal heptad repeats; Derivatives; Dimerization; Dimers; Disulfide bonds; disulfide bridges; Glycoprotein gp41; HIV; HIV-1 fusion inhibitor; Human immunodeficiency virus; Inhibitors; Viral envelope proteins
• ISSN: 1439-4227; 1439-7633
• DOI: 10.1002/cbic.201900187

C34, a 34‐mer fragment peptide, is contained in the HIV‐1 envelope protein gp41. A dimeric derivative of C34 linked through a disulfide bridge at its C terminus was synthesized and found to display potent anti‐HIV activity, comparable with that of a previously reported PEGylated dimer of C34REG. The reduction in the size of the linker moiety for dimerization was thus successful, and this result might shed some light on the mechanism of the suppression of six‐helix bundle formation by these C34 dimeric derivatives. Addition of a Gly‐Cys(CH2CONH2)‐Gly‐Gly motif at the N‐terminal position of a C34 monomeric derivative significantly increased the anti‐HIV‐1 activity. This moiety functions as a new pharmacophore, and this might provide a useful insight into the design of potent HIV‐1 fusion inhibitors. The links effect: A dimeric HIV‐1 C34 derivative linked through a disulfide bridge at the C terminus was synthesized and found to display high anti‐HIV activity, comparable with that of its previously reported PEGylated dimer. This could lead to elucidation of the obscure mechanisms of the suppression of six‐helix bundle formation by dimeric C34 derivatives.