Peptidyl polymers

The synthesis of peptidyl polymers has a long and elegant history, beginning with the construction of homopolypeptides and random copolypeptides. More recently, biomolecules that incorporate peptide entities into classic polymer structures have been created. Sequential peptide polymers have been constructed that model the three-dimensional structure of connective tissue proteins. This article describes methods for the assembly of a variety of peptidyl polymers. 

Once an amino acid is linked to an insoluble polymer, it can be converted to a dipeptide derivative that remains attached to the support while excess starting materials and the by-products of acylation can be removed simply by washing the peptidyl polymer with appropriately selected solvents. Partial deprotection is then carried out in a similar fashion and the dipeptide transformed into a tripeptide while the link between peptide and resin remains intact. In this way the chain can be lengthened until complete, without a single concentration or precipitation or transfer from one container into another. Only addition of reactants and repeated washings are necessary. At the conclusion of the chain building process the bond between peptide and polymer is cleaved and the peptide purified. 

One of the most successful conjugate polymer systems was developed by Duncan and Kopecek (25). The polymer carrier used in their system is poly [N(2-hydroxypropyl) methacrylamide] a biocompatible polymer that was originally developed as a plasma extender. They have evaluated a number of polymer conjugated drugs for cancer chemotherapy with interesting results. The attachment of the drug is through a peptidyl spacer pendent to the polymer backbone. These peptides links are stable in aqueous media but are readily hydrolyzed intracellularly... 

A phase I clinical and pharmacokinetic study of PKl comprising doxorubicin covalently bound to N-(2-hydroxypropyl)-methacrylamide copolymer by a peptidyl linker, was carried out in 36 patients with refractory or resistant cancers [94], PKl demonstrated anti-tumour activity, and that polymer-drug conjugation decreased doxorubicin dose-limiting toxicities. Phase II studies are in progress. 

Designing appropriate polymer-drug linkers for orally administered conjugates is another challenge. Peptidyl sequences tailored for site-specific cleavage by brush border enzymes, i.e., at the enterocyte smface (263), were explored, and also azo hnkers for colon-specific, e.g., of anti-inflammatory agents like aminosalicyfic acid (264). 

The exceptions are peptides containing an N-terminal glutamine residue without side-chain protection and polymer-bound dipeptides—these should be stored Fmoc-protected, in order to prevent intramolecular cyclization. For a period of a few days, the peptidyl resin can be stored swollen in DMF at 5 C. For longer periods, the resin should be stored in the dried state such resins should be re-swollen in DMF for 18 h before use. 

F. Rypdcek, W. R. Banks, D. Noskovd and G. A. Digenis, Synthetic macromolecular inhibitors of human-leukocyte elastase. 1. Synthesis of peptidyl carbamates boimd to water-soluble polymers — poly-a,jS-[N-(2-hydroxyethyl)-D,L-aspartamide] and poly-a-[N -(2-hydroxyethyl)-L-glutamine],/. Med. Chem., 37, 1850-1856 (1994). 

Attention should be given to the similarity between solid phase technology and the biological synthesis of proteins. In both cases, an amino acid is attached via the carboxylate function to a large macromolecular surface upon which the sequential addition of other amino acids and peptide bond formation occurs. In one case, the polymer, like the tRNA molecule at the peptidyl site, is the leaving group, while in the other case, the polymer, like the tRNA molecule at the aminoacyl site, remains bound to the chain after formation... 

Dimcan, et al. " have investigated a number of copolymers having a backbone based on iV-(2-hydroxpropyl)methacrylamide (HPMA, 37). Briefly, sidechains containing various amino acid (peptidyl) spacers are introduced onto the HPMA polymer. These peptidyl sidechains include Gly-Gly and Gly-Phe-Leu-Gly that contain carboxylate or amino end-groups that are reacted with cisplatin. 

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