Cyclic Dipeptides: The Biological and Structural Landscape with Special Focus on the Anti-Cancer Proline-Based Scaffold

Abstract

Cyclic dipeptides, also know as diketopiperazines (DKP), the simplest cyclic forms of peptides widespread in nature, are unsurpassed in their structural and bio-functional diversity. DKPs, especially those containing proline, due to their unique features such as, inter alia, extra-rigid conformation, high resistance to enzyme degradation, increased cell permeability, and expandable ability to bind a diverse of targets with better affinity, have emerged in the last years as biologically pre-validated platforms for the drug discovery. Recent advances have revealed their enormous potential in the development of next-generation theranostics, smart delivery systems, and biomaterials. Here, we present an updated review on the biological and structural profile of these appealing biomolecules, with a particular emphasis on those with anticancer properties, since cancers are the main cause of death all over the world. Additionally, we provide a consideration on supramolecular structuring and synthons, based on the proline-based DKP privileged scaffold, for inspiration in the design of compound libraries in search of ideal ligands, innovative self-assembled nanomaterials, and bio-functional architectures.

Keywords: cyclic dipeptides; diketopiperazines; drug discovery; privileged scaffold; proline-based DKPs; supramolecular structuring.

Figure 1

Structure of 2,3-DKP (left), 2,5-DKP (middle) and 2,6-DKP (right) rings as important pharmacophores.

Figure 2

Crystal structure of cytochrome P450 NasF5053 Q65I-A86G mutant variant from Streptomyces sp. NRRL F-5053 in the cyclo(l-Trp-l-Pro)-bound state; RCSB PDB ref. code: 6VZA.pdb [234]. On the left: The molecular view of supramolecular interactions, showing, e.g., synthon formed by _(DKP)C = O H-N H-bonding interaction.