Total Synthesis and Anti-Hepatitis C Virus Activity of MA026

The first total synthesis of MA026 and the identification of its candidate target protein for anti-hepatitis C virus activity are presented. MA026, a novel lipocyclodepsipeptide isolated from the fermentation broth of Pseudomonas sp. RtIB026, consists of a cyclodepsipeptide, a chain peptide, and an N-terminal (<i>R</i>)-3-hydroxydecanoic acid. The first subunit, side chain <b>2</b>, was prepared by coupling fatty acid moiety <b>4</b> with tripeptide <b>5</b>. The key macrocyclization of the decadepsipeptide at l-Leu¹⁰-d-Gln¹¹ provided the second subunit, cyclodepsipeptide <b>3</b>. Late-stage condensation of the two key subunits and final deprotection afforded MA026. This convergent, flexible, solution-phase synthesis will be invaluable in generating MA026 derivatives for future structure–activity relationship studies. An infectious hepatitis C virus (HCV) cell culture assay revealed that MA026 suppresses HCV infection into host hepatocytes by inhibiting the entry process in a dose-dependent manner. Phage display screening followed by surface plasmon resonance (SPR) binding analyses identified claudin-1, an HCV entry receptor, as a candidate target protein of MA026