Cyclic peptides

Cyclic peptides represent a distinctive class of polypeptide chains characterized by their closed-ring structures, achieved through the formation of stable bonds such as amide, lactone, ether, and others. The ring structure, often formed by linking the amino and carboxyl termini, is a defining feature of cyclic peptides. Notable examples of cyclic peptides found in nature include gramicidin, tyrocidine, cyclosporin A, and vancomycin, each renowned for its bactericidal, immunosuppressive, or antibacterial activities.

One common mode of cyclic peptide formation is the N-to-C (head-to-tail) cyclization, involving the amide bond formation between the amino and carboxyl termini. This structural arrangement is prevalent among biologically active cyclic peptides. Despite being naturally occurring, cyclic peptides have also emerged as promising candidates in drug development.

One of the most famous cyclic peptide drugs is Cyclosporine (also known as Ciclosporin)

Despite the inherent challenges associated with peptide-based drugs, such as poor oral absorption, rapid metabolism by proteolytic enzymes, and limited cell membrane permeability, peptides, including cyclic ones, offer distinct advantages. These advantages include lower toxicity compared to small synthetic molecules, as peptides tend not to accumulate in organs and rapidly degrade into non-toxic amino acid components after fulfilling their therapeutic roles.

In particular, cyclic peptides exhibit unique properties that make them superior drug candidates compared to their linear counterparts. The conformational rigidity of cyclic peptides, as opposed to the flexibility of linear peptides, plays a pivotal role in enhancing their biological activity. This rigidity reduces the entropy term of the Gibbs free energy, leading to improved binding toward target molecules and heightened receptor selectivity.

Moreover, the cyclic structure imparts resistance to hydrolysis by exopeptidases due to the absence of both amino and carboxyl termini. Some cyclic peptides, exemplified by cyclosporin A, demonstrate the ability to cross cell membranes, a feature that was traditionally considered more challenging for linear peptides.

While acknowledging the challenges associated with peptide drugs, the benefits of peptides, particularly cyclic ones, are evident. Their selectivity in interacting with target molecules, reduced toxicity, and enhanced biological activity position cyclic peptides as promising entities in the pharmaceutical landscape. In light of these strengths, the market already boasts various peptide drugs, encompassing receptor agonists and antagonists, peptide hormones and analogs, HIV protease inhibitors, among others. The unique attributes of cyclic peptides, including their conformational rigidity and resistance to enzymatic degradation, underscore their potential to further elevate the status of peptide-based drugs in therapeutic applications.

Classification of cyclic peptides

Homodetic Cyclic Peptides: Notably represented by cyclosporine A, homodetic cyclic peptides exclusively consist of normal peptide bonds. These bonds form between the alpha carboxyl of one residue and the alpha amine of another. The smallest entities within this category are 2,5-diketopiperazines, derived from the cyclization of a dipeptide.

Cyclic Isopeptides: Featuring at least one non-alpha amide linkage, cyclic isopeptides include bonds between the side chain of one residue and the alpha carboxyl group of another. Examples include microcystin and bacitracin.

Cyclic Depsipeptides: Illustrated by aureobasidin A and HUN-7293, cyclic depsipeptides replace at least one amide with a lactone (ester) linkage. Certain instances involve cyclization between the C-terminal carboxyl and the side chain of a Thr or Ser residue, exemplified by kahalalide F, theonellapeptolide, and didemnin B.

Bicyclic Peptides: Amanitins and phalloidins fall under this category, featuring a bridging group typically between two side chains. In amatoxins, a sulfoxide bridge forms between Trp and Cys residues. Other examples include echinomycin, triostin A, and Celogentin C.

Disulfide-Bonded Cyclic Peptides: A subgroup encompasses both bi and monocyclic peptides, with a distinctive disulfide bond linkage between two cysteines. Notable among these is oxytocin.