Chemical Synthesis of an HIV-1 Protease Analog with Some Amides in a Polypeptide Main Chain Replaced by Disulfide Bonds

Abstract

Abstract In this paper, we describe the chemical synthesis of a large artificial protein human immunodeficiency virus type 1 protease (HIV-1 PR) analog with a 115-mer polypeptide chain on which some amide bonds in the main chain have been replaced by disulfide bonds. In this synthesis, a new 3-nitro-2-pyridine (Npy)-sulfenylation agent Npys-OPh(pF), which can form an active disulfide by reaction with a t-Bu protected cysteine residue, was found to be applicable to the efficient and sequential disulfide ligation producing disulfide polypeptides. Two sequential disulfide ligations in three peptide fragments were accomplished for the construction of an HIV-1 PR disulfide analog. In the Trp-containing fragment 2, mesitylenesulfonyl (Mts) protection avoided a side reaction of Npys-OPh(pF), probably at an indole residue. The HIV-1 PR disulfide analog was successfully synthesized from fragment 1 with an isolated yield of 11% by two disulfide ligations of the fragments and the final Mts deprotection of the Trp residue.