Design of Cyclic Peptides - Peptide and Protein Design for Biopharmaceutical Applications - page 134

Figure 4.1 The cyclic peptide cyclosporin A. This natural product is one of the best-
selling drug compounds in the peptidic agent market
bound to its receptor cyclophilin [23], compared to when the isolated
molecule is crystallized or placed in solution [24,25]. Cyclosporin A was
discovered in 1972 and has been used since 1980 to suppress immune
responses when transplants are grafted, and to treat autoimmune-
induced diseases like rheumatoid arthritis.
4.1.3.2 Further medium-sized and larger natural products
Other important natural cyclopeptides in the pharmaceutical market
are vasopressin, oxytocin [27], vancomycin[28]andinsulin[29],as
well as the recently-developed Integrilin [30] (see Section 5.1). Many of
these peptides were originally discovered as hormones and often served
as starting point for drug design (see e.g. somatostatin [31], enkephalin
[32-34] and melanotan [35]). Cyclization of these peptides (except
vancomycin) is achieved via disulfide bonds between two cysteine resi-
dues. In general, disulfide bridging is the most common way to reduce
the conformational space of peptides and proteins in nature. However,
evolution was never - or at least rarely - faced with having to 'construct'
a cyclic peptide that encompasses all important druglike properties,
such as protection against serum enzymes and in particular human