Novel Peptide–Drug Conjugates with Dual Anticancer Activity

O’Flaherty, Siobhán; Luzina, Olga A.; Dyrkheeva, Nadezhda S.; Krier, Ysaline; Leprince, Jérôme; Zakharenko, Alexandra L.; Pokrovsky, Mikhail A.; Pokrovsky, Andrey G.; Lavrik, Olga I.; Salakhutdinov, Nariman F.; Varbanov, Mihayl; Devocelle, Marc; Volcho, Konstantin P.

doi:10.3390/ijms252212411

Open AccessArticle

Novel Peptide–Drug Conjugates with Dual Anticancer Activity

by

Siobhán O’Flaherty

^1,2,*,

Olga A. Luzina

³

,

Nadezhda S. Dyrkheeva

⁴

,

Ysaline Krier

⁵,

Jérôme Leprince

^6,7

,

Alexandra L. Zakharenko

⁴,

Mikhail A. Pokrovsky

⁸,

Andrey G. Pokrovsky

⁸,

Olga I. Lavrik

⁴

,

Nariman F. Salakhutdinov

³,

Mihayl Varbanov

⁵,

Marc Devocelle

^1,2,†

and

Konstantin P. Volcho

^3,8,†

¹

Department of Chemistry, RCSI University of Medicine and Health Sciences, 123, St. Stephen’s Green, D02 YN77 Dublin, Ireland

²

SSPC (Synthesis and Solid State Pharmaceutical Centre) Research Centre, V94 T9PX Limerick, Ireland

³

Department of Medicinal Chemistry, N.N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, 9 Acad. Lavrentjev Ave., 630090 Novosibirsk, Russia

⁴

Institute of Chemical Biology and Fundamental Medicine, SB RAS, 8, Lavrentjev Ave., 630090 Novosibirsk, Russia

⁵

Laboratoire Lorraine de Chimie Moléculaire, Université de Lorraine, CNRS, L2CM, 54000 Nancy, France

⁶

Inserm, Rouen Normandie Université, NorDiC UMR 1239, 76000 Rouen, France

⁷

Rouen Normandie Université, HeRacLes UMS 51, PRIMACEN, 76000 Rouen, France

⁸

V. Zelman Institute for Medicine and Psychology, Novosibirsk State University, 2 Pirogova str., 630090 Novosibirsk, Russia

^*

Author to whom correspondence should be addressed.

^†

These authors contributed equally to this work.

Int. J. Mol. Sci. 2024, 25(22), 12411; https://doi.org/10.3390/ijms252212411

Submission received: 17 October 2024 / Revised: 11 November 2024 / Accepted: 12 November 2024 / Published: 19 November 2024

(This article belongs to the Special Issue Novel Molecular Pathways in Oncology 2.0)

Download

Browse Figures

Versions Notes

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 it remains relatively less explored in the generation of anticancer candidates. In this study, two usnic acid derivatives, based on hydrazinothiazole and benzylidenefuranone pharmacophore moieties, respectively, were 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 reduction in the activity of the parent drugs to their conservation or even enhancement. Notably, the conjugates retained some anti-TDP1 activity and displayed intermediate, or even higher, cytotoxicities against glioblastoma cells, compared to their individual components.

Keywords: antimicrobial peptides; secondary metabolites; peptide–drug conjugates; usnic acid; anticancer

Graphical Abstract

Share and Cite

MDPI and ACS 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.; et al. Novel Peptide–Drug Conjugates with Dual Anticancer Activity. Int. J. Mol. Sci. 2024, 25, 12411. https://doi.org/10.3390/ijms252212411

AMA Style

O’Flaherty S, Luzina OA, Dyrkheeva NS, Krier Y, Leprince J, Zakharenko AL, Pokrovsky MA, Pokrovsky AG, Lavrik OI, Salakhutdinov NF, et al. Novel Peptide–Drug Conjugates with Dual Anticancer Activity. International Journal of Molecular Sciences. 2024; 25(22):12411. https://doi.org/10.3390/ijms252212411

Chicago/Turabian Style

O’Flaherty, Siobhán, Olga A. Luzina, Nadezhda S. Dyrkheeva, Ysaline Krier, Jérôme Leprince, Alexandra L. Zakharenko, Mikhail A. Pokrovsky, Andrey G. Pokrovsky, Olga I. Lavrik, Nariman F. Salakhutdinov, and et al. 2024. "Novel Peptide–Drug Conjugates with Dual Anticancer Activity" International Journal of Molecular Sciences 25, no. 22: 12411. https://doi.org/10.3390/ijms252212411

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. International Journal of Molecular Sciences, 25(22), 12411. https://doi.org/10.3390/ijms252212411

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Menu

Novel Peptide–Drug Conjugates with Dual Anticancer Activity

Abstract

Share and Cite

Article Metrics

Article Access Statistics

Further Information

Guidelines

MDPI Initiatives

Follow MDPI