Version 1
: Received: 25 October 2024 / Approved: 27 October 2024 / Online: 28 October 2024 (12:08:50 CET)
How to cite:
O’Flaherty, S.; Luzina, O. A.; Dyrkheeva, N. S.; Krier, Y.; Leprince, J.; Zakharenko, A. L.; Pokrovsky, M. A.; Pokrovsky, A. G.; Lavrik, O. I.; Salakhutdinov, N. F.; Varbanov, M.; Devocelle, M.; Volcho, K. P. Novel Peptide-Drug Conjugates with Dual Anticancer Activity. Preprints2024, 2024102094. https://doi.org/10.20944/preprints202410.2094.v1
O’Flaherty, S.; Luzina, O. A.; Dyrkheeva, N. S.; Krier, Y.; Leprince, J.; Zakharenko, A. L.; Pokrovsky, M. A.; Pokrovsky, A. G.; Lavrik, O. I.; Salakhutdinov, N. F.; Varbanov, M.; Devocelle, M.; Volcho, K. P. Novel Peptide-Drug Conjugates with Dual Anticancer Activity. Preprints 2024, 2024102094. https://doi.org/10.20944/preprints202410.2094.v1
O’Flaherty, S.; Luzina, O. A.; Dyrkheeva, N. S.; Krier, Y.; Leprince, J.; Zakharenko, A. L.; Pokrovsky, M. A.; Pokrovsky, A. G.; Lavrik, O. I.; Salakhutdinov, N. F.; Varbanov, M.; Devocelle, M.; Volcho, K. P. Novel Peptide-Drug Conjugates with Dual Anticancer Activity. Preprints2024, 2024102094. https://doi.org/10.20944/preprints202410.2094.v1
APA Style
O’Flaherty, S., Luzina, O. A., Dyrkheeva, N. S., Krier, Y., Leprince, J., Zakharenko, A. L., Pokrovsky, M. A., Pokrovsky, A. G., Lavrik, O. I., Salakhutdinov, N. F., Varbanov, M., Devocelle, M., & Volcho, K. P. (2024). Novel Peptide-Drug Conjugates with Dual Anticancer Activity. Preprints. https://doi.org/10.20944/preprints202410.2094.v1
Chicago/Turabian Style
O’Flaherty, S., Marc Devocelle and Konstantin P Volcho. 2024 "Novel Peptide-Drug Conjugates with Dual Anticancer Activity" Preprints. https://doi.org/10.20944/preprints202410.2094.v1
Abstract
Cationic Antimicrobial Peptides (AMPs), also called Host Defence Peptides have established antimicrobial and anticancer activities. Conjugation of an AMP to a bioactive molecule with complementary activity can address some of the clinical limitations of the peptide candidate. This approach has been particularly applied in antimicrobial applications of AMPs, but remains relatively less explored in the generation of anticancer candidates. Herein, two usnic acid derivatives, based on hydrazinothiazole and benzylidenefuranone pharmacophore moieties, respectively, have been conjugated to L-K6, a lysine/leucine rich AMP, through a new pyrazole ligation intrinsically driven by the cargo molecule. Both components, the usnic acid derivative and the peptide, are selectively active against cancer cells, by targeting the human DNA repair enzyme tyrosyl-DNA phosphodiesterase 1 (TDP1) and through DNA damage, respectively. The two conjugates, based on a hydrazone linkage, exhibited pleiotropic effects, ranging from, overall, reduction of the activity from the parent drugs to their conservation or even enhancement. Notably, the conjugates retain some anti-TDP1 activity and display intermediate, or even higher, cytotoxicities against glioblastoma cells, compared to their individual components.
Chemistry and Materials Science, Medicinal Chemistry
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.
