Hexapeptides from mammalian inhibitory hormone hunt activate and inactivate nematode reproduction.

Autor: Hart JE; Endocrine Pharmaceuticals, Wilderness End, Tadley, Hampshire, United Kingdom., Mohan S; Division of Nematology, ICAR-Indian Agricultural Research Institute, New Delhi, India., Davies KG; School of Life and Medical Sciences, University of Hertfordshire, College Lane, Hatfield, United Kingdom., Ferneyhough B; Systems Biology Laboratory UK, Abingdon, Oxfordshire, United Kingdom., Clarke IJ; School of Agriculture and Veterinary Science, Melbourne University, Parkville, Victoria, Australia., Hunt JA; Medical Technologies and Advanced Materials, School of Science and Technology, Nottingham Trent University, Nottingham, United Kingdom.; College of Biomedical Engineering, China Medical University, Taichung, Taiwan., Shnyder SD; Institute of Cancer Therapeutics, University of Bradford, Bradford, United Kingdom., Mundy CR; Endocrine Pharmaceuticals, Wilderness End, Tadley, Hampshire, United Kingdom., Howlett DR; Wolfson Centre for Age Related Disease. King's College London, London, United Kingdom., Newton RP; Biochemistry Group, Institute of Life Sciences, Medical School, Swansea University, Swansea, United Kingdom.
Jazyk: angličtina
Zdroj: PloS one [PLoS One] 2022 Dec 01; Vol. 17 (12), pp. e0278049. Date of Electronic Publication: 2022 Dec 01 (Print Publication: 2022).
DOI: 10.1371/journal.pone.0278049
Abstrakt: Background: Biopurification has been used to disclose an evolutionarily conserved inhibitory reproductive hormone involved in tissue mass determination. A (rat) bioassay-guided physicochemical fractionation using ovine materials yielded via Edman degradation a 14-residue amino acid (aa) sequence. As a 14mer synthetic peptide (EPL001) this displayed antiproliferative and reproduction-modulating activity, while representing only a part of the native polypeptide. Even more unexpectedly, a scrambled-sequence control peptide (EPL030) did likewise.
Methods: Reproduction has been investigated in the nematode Steinernema siamkayai, using a fermentation system supplemented with different concentrations of exogenous hexapeptides. Peptide structure-activity relationships have also been studied using prostate cancer and other mammalian cells in vitro, with peptides in solution or immobilized, and via the use of mammalian assays in vivo and through molecular modelling.
Results: Reproduction increased (x3) in the entomopathogenic nematode Steinernema siamkayai after exposure to one synthetic peptide (IEPVFT), while fecundity was reduced (x0.5) after exposure to another (KLKMNG), both effects being dose-dependent. These hexamers are opposite ends of the synthetic peptide KLKMNGKNIEPVFT (EPL030). Bioactivity is unexpected as EPL030 is a control compound, based on a scrambled sequence of the test peptide MKPLTGKVKEFNNI (EPL001). EPL030 and EPL001 are both bioinformatically obscure, having no convincing matches to aa sequences in the protein databases. EPL001 has antiproliferative effects on human prostate cancer cells and rat bone marrow cells in vitro. Intracerebroventricular infusion of EPL001 in sheep was associated with elevated growth hormone in peripheral blood and reduced prolactin. The highly dissimilar EPL001 and EPL030 nonetheless have the foregoing biological effects in common in mammalian systems, while being divergently pro- and anti-fecundity respectively in the nematode Caenorhabditis elegans. Peptides up to a 20mer have also been shown to inhibit the proliferation of human cancer and other mammalian cells in vitro, with reproductive upregulation demonstrated previously in fish and frogs, as well as nematodes. EPL001 encodes the sheep neuroendocrine prohormone secretogranin II (sSgII), as deduced on the basis of immunoprecipitation using an anti-EPL001 antibody, with bespoke bioinformatics. Six sSgII residues are key to EPL001's bioactivity: MKPLTGKVKEFNNI. A stereospecific bimodular tri-residue signature is described involving simultaneous accessibility for binding of the side chains of two specific trios of amino acids, MKP & VFN. An evolutionarily conserved receptor is conceptualised having dimeric binding sites, each with ligand-matching bimodular stereocentres. The bioactivity of the 14mer control peptide EPL030 and its hexapeptide progeny is due to the fortuitous assembly of subsets of the novel hormonal motif, MKPVFN, a default reproductive and tissue-building OFF signal.
Competing Interests: JEH is founding scientist of Endocrine Pharmaceuticals of Hampshire, UK (Company No: 03005721) and an employee of the company. The following authors hold share options in Endocrine: KGD, IJC, JAH, CRM, DRH & RPN. Endocrine has applied for a patent relating to material pertinent to the present article: Hart JE (2021) Hormonal Derivatives. GB Patent Application No. 2112385.6. This does not alter the authors’ adherence to PLOS ONE policies on sharing data and materials.
(Copyright: © 2022 Hart et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)
Databáze: MEDLINE
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