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.

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