Biologically active analogues of naturally occurring peptides

There are at least three general approaches to the synthesis of biologically active peptides or peptidomimetics. The first one concerns the synthesis of naturally occurring peptides containing unusual amino acids, whose availability from natural sources is too scarce for practical purposes. Apart from the need of a high yielding overall synthetic strategy, a methodology for the preparation of the unusual residues is also generally requested. On the other hand, one could be interested in the synthesis of modified versions of certain bioactive peptides, by substitution of the normal amino acids with unusual groups, aiming to obtain analogues displaying enhanced performances in term of activity, duration, etc. Finally, the search for promising drug leads for the development of potential therapeutic agents often requires the synthesis of new molecules, designed on the basis of native peptides, in which the peptidic part is no longer predominant. In this lecture, selected examples of each approach are given. The first part concerns the synthesis of fragments of lysobactin skeleton, a cyclic depsipeptide antibiotic containing five hydroxyamino acids, by way of the chemistry of aziridines and oxazolines.1 The second example describes the synthesis and the pharmacological characterization of analogues on endomorphin-1, a neuropeptide involved in the modulation of pain transmission, as potential analgesics devoid of secondary effects.2 Finally, the last part of the speech is related to the design of non peptidic RGD-sequence-mimetics as iintegrin-antagonists,3 based on dihydropyridinone scaffolds.