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| - Orthogonal Ligation of Unprotected Peptide Segments throughPseudoproline Formation for the Synthesis of HIV-1 ProteaseAnalogs,
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| - We describe the total synthesis of three active HIV-1 proteaseanalogs by an orthogonal ligation throughthiaproline formation of two large, unprotected peptide segments.The central element of this strategy in achievingorthogonality of peptide bond formation is through proximity effect,and the key reaction is a side chain thiol initiatedaldehyde capture to overcome the entropic problem of coupling betweentwo large molecular weight peptide segments.The capture step also leads to specific entropic activation of theacyl segment because the respective termini arebrought to close proximity, resulting in a spontaneous acylrearrangement to form the amide bond. A generalmethodusing a thioester for introducing an aldehyde moiety to the C-terminusof an unprotected peptide segment was alsodeveloped. Three active analogs of HIV-1 protease were obtained inexcellent yield by ligating two segments of 38and 61 residues. Two analogs contained a thioproline residue atposition 39, and the third contained a 38−39 non-peptide backbone. Efficient ligation at pH 4 was attained atpeptide segment concentrations as low as 50 μM, aconcentration which is not feasible with conventional convergentmethods using protected peptide segments.
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