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.

Antiviral Activity of a Cyclic Pro-Pro-β3-HoPhe-Phe Tetrapeptide against HSV-1 and HAdV-5

“…Thus, the mechanism of 4B8M action can be responsible for the mediation of its several therapeutic properties, such as anti-inflammatory, antiviral and antitumor. The application of cyclic peptides, unlike linear ones, has obvious therapeutic advantages due to their resistance to proteolysis and increased cell membrane permeability [ 33 , 34 ]. The 4B8M peptide appeared to be very effective when applied in an ointment for the amelioration of inflammatory skin changes [ 5 ].…”

Phytochemical Profile and Anticancer Potential of Endophytic Microorganisms from Liverwort Species, Marchantia polymorpha L.

“…Proline is linked to diverse plant stresses as defense against toxicity. It improves the formation of reactive oxygen species, signaling, and cellular apoptosis [ 22 ]. Diketopiperazines have been isolated from Aspergillus niger , inhabiting the liverwort Heteroscyphus tener .…”

Structural and Biofunctional Insights into the Cyclo(Pro-Pro-Phe-Phe-) Scaffold from Experimental and In Silico Studies: Melanoma and Beyond

“…Notably, the determination of the three-dimensional (3D) structure is essential either for rational drug design and development or for the identification of new targets. Therefore, here we present the first model crystal structure of tetrapeptide cyclo(Pro-Pro-β 3 homoPhe-Phe-), called 4B8M, [IUPAC name: (3S,9S,13S,16S)-9,13-dibenzyl-1,7,10,14-tetraazatricyclo[14.3.0.03,7]nonadecane-2,8,11,15-tetrone], together with comparative ancillary analysis towards YEPVIZ [39], in line with our interest on (supra)molecular exploration of peptide-based molecules [11,12,25,29,. In this context, the results of complex Hirshfeld surface investigations on interatomic contacts, electrostatic and energetic features, as well as density functional theory (DFT) are discussed.…”

“…More specifically, cyclo(Leu-Ile-Ile-Leu-Val-Pro-Pro-Phe-Phe-), denoted as CLA; cyclo(Pro-Proβ 3 homoPhe-Phe-), as 4B8M; cyclo(Pro-Pro-β 3 homoPhe-Phe-Pro-Pro-β 3 homoPhe-Phe-), 4B8D; cyclo(Pro-homoPro-β 3 homoPhe-Phe-), as P11; H-Pro-homoPro-β 3 homoPhe-Phe-OH, P11L; H-D-Pro-Pro-β 3 homoPhe-Phe-OH, as P03L, H-Pro-Pro-D-β 3 homoPhe-Phe-OH, as P04L were investigated. In addition, cyclo(Phe-Phe-), denoted as DKP1, was included in the analysis because of the proven anticancer activity of cyclic dipeptides, including melanoma [29,30].…”