Orthogonal Ligation of Unprotected Peptide Segments through Pseudoproline Formation for the Synthesis of HIV-1 Protease Analogs,

Abstract

We describe the total synthesis of three active HIV-1 protease analogs by an orthogonal ligation through thiaproline formation of two large, unprotected peptide segments. The central element of this strategy in achieving orthogonality of peptide bond formation is through proximity effect, and the key reaction is a side chain thiol initiated aldehyde capture to overcome the entropic problem of coupling between two large molecular weight peptide segments. The capture step also leads to specific entropic activation of the acyl segment because the respective termini are brought to close proximity, resulting in a spontaneous acyl rearrangement to form the amide bond. A general method using a thioester for introducing an aldehyde moiety to the C-terminus of an unprotected peptide segment was also developed. Three active analogs of HIV-1 protease were obtained in excellent yield by ligating two segments of 38 and 61 residues. Two analogs contained a thioproline residue at position 39, and the third contained a 3...