The influence of the side‐chain sequence on the structure–activity correlations of immunomodulatory branched polypeptides. Synthesis and conformational analysis of new model polypeptides

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Abstract
New branched polypeptides were synthesized for a detailed study of the influence of the side‐chain structure on the conformation and biological properties. The first subset of polypeptides were prepared by coupling of tetrapeptides to poly[L‐Lys]. These polymers contain either DL‐Ala3‐X {poly[Lys‐(X‐DL‐Ala3)n]} X‐DL‐Ala3 {poly[Lys‐(DL‐Ala3‐X)n] (n ≤ 1)} tetrapeptide side chains. Another group of branched polymers comprise a mixture of DL‐Alam and of DL‐Alam‐X oligomeric branches in a random distribution {poly[Lys‐(DL‐Alam‐Xi)](i < 1, m ∼ 3)}. In each subset the X = Leu or Phe derivatives were prepared. The N‐protected tetrapeptides were synthesized by conventional liquid phase methods and were coupled as active esters. The degree of racemization was found relatively high both for active esters and coupled derivatives, when optically active amino acids were in the C‐terminal position of the tetrapeptides. In the case of the poly[Lys‐(Leu‐DL‐Ala3)n] derivative, comparative experiments were carred out using various methodical alterations. The highest stereochemical homogeniety could be achieved when the tetrapeptide active ester was synthesized by the “backing off” method. CD spectra of poly[Lys‐(Xi‐DL‐Alam)] (i < 1, m ∼ 3) and of poly[Lys‐(X‐DL‐Ala3)n] were analyzed and compared to those of poly[Lys‐(DL‐Ala3‐Xi)] and of poly[Lys‐(DL‐Ala3‐X)n]. All measurements were performed in water solutions of varying pH values and ionic strengths. The data obtained suggest that branched polypeptides containing a mixture of two different types of oligomeric side chains (DL‐Alam and DL‐Alam‐Xi or Xi‐DL‐Alam) distributed randomly adopt an almost indentical conformation to those that comprise only the respective tetrapeptide (DL‐Ala3‐X or X‐DL‐Ala3) branches. The results also indicate that the tendency to form an ordered structure is determined by the indentity and the position of the chiral amino acid X (Phe or Leu) in the side chain.