TY  - JOUR
AU  - Naamneh, Majdi Saleem
AU  - Momić, Tatjana
AU  - Klazas, Michal
AU  - Grosche, Julius
AU  - Eble, Johannes A.
AU  - Marcinkiewicz, Cezary
AU  - Khazanov, Netaly
AU  - Senderowitz, Hanoch
AU  - Hoffman, Amnon
AU  - Gilon, Chaim
AU  - Katzhendler, Jehoshua
AU  - Lazarovici, Philip
PY  - 2024
UR  - https://vinar.vin.bg.ac.rs/handle/123456789/13297
AB  - 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,
which 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 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
an 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.
T2  - Pharmaceuticals
T1  - 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
VL  - 17
IS  - 5
SP  - 549
DO  - 10.3390/ph17050549
ER  - 

@article{
author = "Naamneh, Majdi Saleem and Momić, Tatjana and Klazas, Michal and Grosche, Julius and Eble, Johannes A. and Marcinkiewicz, Cezary and Khazanov, Netaly and Senderowitz, Hanoch and Hoffman, Amnon and Gilon, Chaim and Katzhendler, Jehoshua and Lazarovici, Philip",
year = "2024",
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,
which 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 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
an 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.",
journal = "Pharmaceuticals",
title = "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",
volume = "17",
number = "5",
pages = "549",
doi = "10.3390/ph17050549"
}

Naamneh, M. S., Momić, T., Klazas, M., Grosche, J., Eble, J. A., Marcinkiewicz, C., Khazanov, N., Senderowitz, H., Hoffman, A., Gilon, C., Katzhendler, J.,& Lazarovici, P.. (2024). 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. in Pharmaceuticals, 17(5), 549.
https://doi.org/10.3390/ph17050549

Naamneh MS, Momić T, Klazas M, Grosche J, Eble JA, 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. in Pharmaceuticals. 2024;17(5):549.
doi:10.3390/ph17050549 .

Naamneh, Majdi Saleem, Momić, Tatjana, Klazas, Michal, Grosche, Julius, Eble, Johannes A., Marcinkiewicz, Cezary, Khazanov, Netaly, Senderowitz, Hanoch, Hoffman, Amnon, Gilon, Chaim, Katzhendler, Jehoshua, Lazarovici, Philip, "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" in Pharmaceuticals, 17, no. 5 (2024):549,
https://doi.org/10.3390/ph17050549 . .