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ORIGINAL RESEARCH article

Front. Pharmacol.
Sec. Experimental Pharmacology and Drug Discovery
Volume 15 - 2024 | doi: 10.3389/fphar.2024.1408091
This article is part of the Research Topic The Magic Bullet Evolution in Tumor Therapy: Novel Drug Conjugates for Targeted Delivery View all 8 articles

Development of bombesin-tubulysin conjugates using multicomponent chemistry to functionalize both the payload and the homing peptide

Provisionally accepted
Dayma Llanes Dayma Llanes 1Robert Rennert Robert Rennert 1Paul Jänicke Paul Jänicke 1Ibrahim Morgan Ibrahim Morgan 1Leslie Reguera Leslie Reguera 2Daniel G. Rivera Daniel G. Rivera 2*Manuel G. Ricardo Manuel G. Ricardo 1Ludger A. Wessjohann Ludger A. Wessjohann 1
  • 1 Leibniz Institute of Plant Biochemistry, Halle, Saxony-Anhalt, Germany
  • 2 University of Havana, Havana, La Habana, Cuba

The final, formatted version of the article will be published soon.

    Peptide-drug conjugates (PDCs) have recently gained significant attention for the targeted delivery of anticancer therapeutics, mainly due to their cost-effective and chemically defined production and lower antigenicity compared to ADCs, among other benefits. In this study, we designed and synthesized novel PDCs by conjugating new thiol-functionalized tubulysin analogs (tubugis) to bombesin, a peptide ligand with a relevant role in cancer research. Two tubulysin analogs bearing ready-for-conjugation thiol groups were prepared by an on-resin multicomponent peptide synthesis strategy and subsequently tested for their stand-alone in vitro anti-proliferative activity against human cancer cells, which resulted in IC50 values in the nanomolar range. In addition, various fluorescently labeled [K 5 ]-bombesin(6-14) peptides, nonlipidated and lipidated with fatty acid chains of variable length, were also synthesized using the versatile multicomponent chemistry. These bombesin derivatives were tested for their gastrinrelated peptide receptor (GRPR)-mediated internalization into cancer cells using flow cytometry, proving that the lipid tail (specially C14) enhances the cell internalization. Using the tubugi toxins and bombesin peptides, three different bombesin-tubugi conjugates were synthesized with different cleavage propensity and lipophilicity. Preliminary in vitro experiments revealed that, depending on the linker and the presence of a lipid tail, these novel PDCs possess good to potent anticancer activity and moderate selectivity for GRPRoverexpressing cancer cells.

    Keywords: Anticancer agents, Peptide-drug conjugates (PDCs), tubulysin therapy, Lipopeptides, Gastrin-releasing peptide (GRP) receptor, Bombesin (BBN), bombesin receptor

    Received: 27 Mar 2024; Accepted: 18 Oct 2024.

    Copyright: © 2024 Llanes, Rennert, Jänicke, Morgan, Reguera, Rivera, Ricardo and Wessjohann. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

    * Correspondence: Daniel G. Rivera, University of Havana, Havana, 10400, La Habana, Cuba

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