Reniochalistatin E: A potentiating agent and a potential novel drug delivery platform

IF 4.5 2区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Bioorganic Chemistry Pub Date : 2025-03-01 DOI:10.1016/j.bioorg.2025.108331

Kameron R. Wildeman, Matthew Barnett, Anthony Fatino, Chamitha Weeramange, Ryan J. Rafferty

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Abstract

Peptides, both linear and cyclic, have begun to emerge as a viable therapeutic for the treatment of various diseases. As such, synthesizing these linear and macrocyclic peptides as natural product targets or related structural analogs can help us to understand their biological importance. Reniochalistatin E is a proline-rich macrocyclic peptide natural product first synthesized in 2017 by our laboratory, and screening against various cancerous cell lines revealed moderate to low cytotoxicity as a sole agent. We next became interested in studying this compound as a potentiating agent to identify any synergistic effects. Indeed, reniochalistatin E was unveiled to show potential intramolecular pi-stacking that enhanced the cytotoxicity of clinically used anti-cancer agents. To exploit this unique characteristic, attention was directed towards the modification of the tryptophan residue to enhance the synergistic effect with additional cytotoxic agents. To this, a phenylalanine-tryptophan exchange was undertaken to probe this hypothesis and was found to possess no detectable cytotoxicity variation. Together, the data collected supports further exploration with drug conjugate handles en route towards a novel drug delivery platform.

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来源期刊

Bioorganic Chemistry 生物-生化与分子生物学

CiteScore

9.70

自引率

3.90%

发文量

679

审稿时长

31 days

期刊介绍： Bioorganic Chemistry publishes research that addresses biological questions at the molecular level, using organic chemistry and principles of physical organic chemistry. The scope of the journal covers a range of topics at the organic chemistry-biology interface, including: enzyme catalysis, biotransformation and enzyme inhibition; nucleic acids chemistry; medicinal chemistry; natural product chemistry, natural product synthesis and natural product biosynthesis; antimicrobial agents; lipid and peptide chemistry; biophysical chemistry; biological probes; bio-orthogonal chemistry and biomimetic chemistry. For manuscripts dealing with synthetic bioactive compounds, the Journal requires that the molecular target of the compounds described must be known, and must be demonstrated experimentally in the manuscript. For studies involving natural products, if the molecular target is unknown, some data beyond simple cell-based toxicity studies to provide insight into the mechanism of action is required. Studies supported by molecular docking are welcome, but must be supported by experimental data. The Journal does not consider manuscripts that are purely theoretical or computational in nature. The Journal publishes regular articles, short communications and reviews. Reviews are normally invited by Editors or Editorial Board members. Authors of unsolicited reviews should first contact an Editor or Editorial Board member to determine whether the proposed article is within the scope of the Journal.