Synthesis, conformation, and bioactivity of novel analogues of the antiviral lipopeptide halovir A.

We synthesized by solution-phase methods three analogues, [L-Leu(6)-OMe], [L-(alphaMe)Leu(3), L-Leu(6)-OMe], and [L-(alphaMe)Val(4), L-Leu(6)-OMe] of halovir A. The [L-Leu(6)-OMe] analogue is known to be biologically equipotent to its naturally occurring, antiviral, lipopentapeptide amide parent compound. The preferred conformations of the L-(alphaMe)Leu- and L-(alphaMe)Val-containing analogues, with a potentially reinforced helicity, were compared with those of [L-Leu(6)-OMe] halovir A and the natural peptide itself by use of a combination of FT-IR absorption and NMR techniques. Measurements of the antiviral activities against herpes simplex virus type-1 (HSV-1) of halovir A and its three analogues were also carried out. Interestingly, the [L-(alphaMe)Val(4), L-Leu(6)-OMe] analogue exhibits the most significant activity in reducing HSV-1 infectivity, notably higher than that of halovir A itself.