Preprint Article Version 1 Preserved in Portico This version is not peer-reviewed

Structure-Activity Relationship of Synthetic Linear KTS-Peptides Containing Meta-Aminobenzoic Acid as Antagonists of α1β1 Integrin with Antiangiogenic and Melanoma’ Antitumor Activities

Majdi Saleem Naamneh
ORCID logo ,
Tatjana Momic
,
Michal Klazas
,
Julius Grosche
,
Johannes A Eble
,
Cezary Marcinkiewicz
,
Netaly Khazanov
,
Hanoch Senderowitz
ORCID logo ,
Amnon Hoffman
ORCID logo ,
Chaim Gilon
,
Jehoshua Katzhendler
,
Philip Lazarovici
* ORCID logo
Version 1 : Received: 8 April 2024 / Approved: 9 April 2024 / Online: 9 April 2024 (09:51:33 CEST)

A peer-reviewed article of this Preprint also exists.

Naamneh, M.S.; Momic, T.; Klazas, M.; Grosche, J.; Eble, J.A.; Marcinkiewicz, C.; Khazanov, N.; Senderowitz, H.; Hoffman, A.; Gilon, C.; Katzhendler, J.; Lazarovici, P. Structure–Activity Relationship of Synthetic Linear KTS-Peptides Containing Meta-Aminobenzoic Acid as Antagonists of α1β1 Integrin with Anti-Angiogenic and Melanoma Anti-Tumor Activities. Pharmaceuticals 2024, 17, 549. Naamneh, M.S.; Momic, T.; Klazas, M.; Grosche, J.; Eble, J.A.; Marcinkiewicz, C.; Khazanov, N.; Senderowitz, H.; Hoffman, A.; Gilon, C.; Katzhendler, J.; Lazarovici, P. Structure–Activity Relationship of Synthetic Linear KTS-Peptides Containing Meta-Aminobenzoic Acid as Antagonists of α1β1 Integrin with Anti-Angiogenic and Melanoma Anti-Tumor Activities. Pharmaceuticals 2024, 17, 549.

Abstract

To develop peptide drugs targeting integrin receptors, synthetic peptide ligands endowed with well-defined selective binding motifs are necessary. The snake venom KTS-containing disintegrins, that selectively block collagen α1β1 integrin, were used as lead compounds for the synthesis and structure-activity relationship of a series of linear peptides containing the KTS-pharmacophore and alternating natural amino acids and 3-aminobenzoic acid (MABA). To ensure a better stiffness and metabolic stability, one, two and three MABA residues, were introduced around the KTS pharmacophore motif. Molecular dynamics simulations have determined that the solution conformation of MABA peptide 4 is more compact, underwent larger conformational changes until convergence, and spent most of the time in a single cluster. The peptides’ binding affinity has been characterized by enzyme linked immunosorbent assay in which the most potent peptide 4 inhibited with IC50 of 324±8 µM and 550±45 µM the binding of GST-α1-A domain to collagen IV fragment CB3, and the cell adhesion to collagen IV using α1-overexpressor cells, respectively. Docking studies and MM-GBSA calculations confirmed that peptide 4 binds a smaller region of the integrin near the collagen- binding site and penetrated deeper into the binding site near Trp1. Peptide 4, inhibited tube formation by endothelial cell migration in the Matrigel angiogenesis in vitro assay. Peptide 4 was acutely tolerated by mice, showed stability in human serum, decreased tumor volume and angiogenesis, and significantly increased the survival of mice injected with B16 melanoma cells. These findings propose that MABA-peptide 4 can further serve as an α1β1-integrin antagonist lead compound for further drug-optimization in angiogenesis and cancer therapy.

Keywords

MABA; KTS; peptide synthesis; modeling; conformation; stability; integrin α1; cell adhesion; angiogenesis; melanoma tumor

Subject

Medicine and Pharmacology, Medicine and Pharmacology

Copyright: This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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