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Conjugation of HS-Oligopeptides with Polymeric Branched Chain Polypeptides Containing Multiple Amino Groups

Research Group for Peptide Chemistry, Hungarian Academy of Science, Eötvös L. University, P.O. Box 32, Budapest 112, Hungary H-1518

Andrea Dancs

Research Group for Peptide Chemistry, Hungarian Academy of Science, Eötvös L. University, P.O. Box 32, Budapest 112, Hungary H-1518

György Kóczán

Research Group for Peptide Chemistry, Hungarian Academy of Science, Eötvös L. University, P.O. Box 32, Budapest 112, Hungary H-1518

Gábor Mezö

Research Group for Peptide Chemistry, Hungarian Academy of Science, Eötvös L. University, P.O. Box 32, Budapest 112, Hungary H-1518

Ferenc Hudecz

Research Group for Peptide Chemistry, Hungarian Academy of Science, Eötvös L. University, P.O. Box 32, Budapest 112, Hungary H-1518

For the preparation of bioconjugates containing polymeric polypeptides with well-defined structure and composition, we systematically studied 3-(2-pyridyldithio)propionic acid N-hydroxy-succinimide ester (SPDP). SPDP as amino- and thiol-reactive heterobifunctional coupling agent is mainly used for protein-based conjugates, and very little data are available on its application for the modification of polymers. In this communication, we describe the effect of polymer/oligopeptide structure and of the reaction condition on the incorporation of oligopeptides with free thiol group (CAVKDEL, CTGRGDSP) into polymeric polypeptides possessing multiple amino groups. For these studies, linear poly[l-lysine] with free -amino groups and its XAK-type branched polypeptide derivatives {poly[Lys(X_i-dl-Ala_m)](i < 1, m 3, XAK)} either with polycationic character {X = (AK), X = Ser (SAK)} or with amphoteric nature {X = Glu (EAK)} were utilized. First, the polymers were modified with SPDP under various conditions, and the degree of substitution was determined. We found that the efficacy of the nucleophilic substitution of NH₂ groups with SPDP depended not only on the pH and the concentration of the coupling reagent but also on the polymer composition, mainly on the pK_a of the branch-terminal amino group of the polymers. SPDP-modified polymeric polypeptides were reacted with the HS-oligopeptides, and the effects of polymer/oligopeptide structure as well as the reaction conditions (pH, peptide/(SSP)polymer molar ratio) on the composition of the product were evaluated. The results suggest that acidic pH is more favorable for the thiol-disulphide exchange, and the side chain composition of the polymers had a pronounced effect while the chemical structure of oligopeptides had only moderate influence on the average degree of substitution.

Journal of Bioactive and Compatible Polymers, Vol. 15, No. 2, 139-154 (2000)
DOI: 10.1177/088391150001500203


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