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

Joanna Bojarska; Martin Breza; Milan Remko; Malgorzata Czyz; Anna Gajos-Michniewicz; Michał Zimecki; Krzysztof Kaczmarek; Izabela D Madura; Jakub M Wojciechowski; Wojciech M Wolf

doi:10.3390/ijms23137173

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

Int J Mol Sci. 2022 Jun 28;23(13):7173. doi: 10.3390/ijms23137173.

Authors

Affiliations

¹ Institute of General and Ecological Chemistry, Faculty of Chemistry, Lodz University of Technology, 116 Zeromskiego Street, 90-924 Lodz, Poland.
² Department of Physical Chemistry, Slovak Technical University, Radlinskeho 9, SK-81237 Bratislava, Slovakia.
³ Remedika, Luzna 9, SK-85104 Bratislava, Slovakia.
⁴ Department of Molecular Biology of Cancer, Medical University of Lodz, 6/8 Mazowiecka Street, 92-215 Lodz, Poland.
⁵ Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, 12 Weigla Street, 53-112 Wroclaw, Poland.
⁶ Institute of Organic Chemistry, Faculty of Chemistry, Lodz University of Technology, 116 Żeromskiego Street, 90-924 Lodz, Poland.
⁷ Faculty of Chemistry, Warsaw University of Technology, 3 Noakowskiego Street, 00-664 Warsaw, Poland.
⁸ Rigaku Europe SE, Hugenottenallee 167, 63263 Neu-Isenburg, Germany.

Abstract

Short peptides have great potential as safe and effective anticancer drug leads. Herein, the influence of short cyclic peptides containing the Pro-Pro-Phe-Phe sequence on patient-derived melanoma cells was investigated. Cyclic peptides such as cyclo(Leu-Ile-Ile-Leu-Val-Pro-Pro-Phe-Phe-), called CLA, and cyclo(Pro-homoPro-β³homoPhe-Phe-), called P11, exert the cytotoxic and the cytostatic effects in melanoma cells, respectively. CLA was the most active peptide as it reduced the viability of melanoma cells to 50% of control at about 10 µM, whereas P11 at about 40 µM after 48 h incubation. Interestingly, a linear derivative of P11 did not induce any effect in melanoma cells confirming previous studies showing that cyclic peptides exert better biological activity compared to their linear counterparts. According to in silico predictions, cyclic tetrapeptides show a better pharmacokinetic and toxic profile to humans than CLA. Notably, the spatial structure of those peptides containing synthetic amino acids has not been explored yet. In the Cambridge Structural Database, there is only one such cyclic tetrapeptide, cyclo((R)-β²homoPhe-D-Pro-Lys-Phe-), while in the Protein Data Bank-none. Therefore, we report the first crystal structure of cyclo(Pro-Pro-β³homoPhe-Phe-), denoted as 4B8M, a close analog of P11, which is crucial for drug discovery. Comparative molecular and supramolecular analysis of both structures was performed. The DFT findings revealed that 4B8M is well interpreted in the water solution. The results of complex Hirshfeld surface investigations on the cooperativity of interatomic contacts in terms of electrostatic and energetic features are provided. In short, the enrichment ratio revealed O^…H/H^…O and C^…H/H^…C as privileged intercontacts in the crystals in relation to basic and large supramolecular H-bonding synthon patterns. Furthermore, the ability of self-assemble 4B8M leading to a nanotubular structure is also discussed.

Keywords: DFT; Hirshfeld surface; electrostatic potential; energy frameworks; homo amino acids; melanoma; short peptides.

MeSH terms

Dipeptides
Humans
Melanoma* / drug therapy
Peptides
Peptides, Cyclic* / chemistry
Peptides, Cyclic* / pharmacology

Substances

Dipeptides
Peptides
Peptides, Cyclic
prolyl-proline
phenylalanylphenylalanine

Grants and funding

The biological part of the studies has been supported by the research funding of Medical University of Lodz (503/1-156-01/503-11-001).