Synthetic Antibiotic Derived from Sequences Encrypted in a Protein from Human Plasma
Cesaro, Angela; Torres, Marcelo D T; Gaglione, Rosa; Dell'Olmo, Eliana; Di Girolamo, Rocco; Bosso, Andrea; Pizzo, Elio; Haagsman, Henk P; Veldhuizen, Edwin J A; de la Fuente-Nunez, Cesar; Arciello, Angela
(2022) ACS Nano, volume 16, issue 2, pp. 1880 - 1895
(Article)
Abstract
Encrypted peptides have been recently found in the human proteome and represent a potential class of antibiotics. Here we report three peptides derived from the human apolipoprotein B (residues 887-922) that exhibited potent antimicrobial activity against drug-resistant Klebsiella pneumoniae, Acinetobacter baumannii, and Staphylococci both in vitro and in an animal
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model. The peptides had excellent cytotoxicity profiles, targeted bacteria by depolarizing and permeabilizing their cytoplasmic membrane, inhibited biofilms, and displayed anti-inflammatory properties. Importantly, the peptides, when used in combination, potentiated the activity of conventional antibiotics against bacteria and did not select for bacterial resistance. To ensure translatability of these molecules, a protease resistant retro-inverso variant of the lead encrypted peptide was synthesized and demonstrated anti-infective activity in a preclinical mouse model. Our results provide a link between human plasma and innate immunity and point to the blood as a source of much-needed antimicrobials.
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Keywords: anti-infective activity, antibiotic resistance, drug discovery, encrypted peptides, human apolipoprotein B, nanopeptides, retro-inverso peptide design, Taverne, General Materials Science, General Engineering, General Physics and Astronomy
ISSN: 1936-0851
Publisher: American Chemical Society
Note: Funding Information: C.F.-N. holds a Presidential Professorship at the University of Pennsylvania, is a recipient of the Langer Prize by the AIChE Foundation, and acknowledges funding from the Institute for Diabetes, Obesity, and Metabolism, the Penn Mental Health AIDS Research Center of the University of Pennsylvania, the Nemirovsky Prize, and the Dean?s Innovation Fund from the Perelman School of Medicine at the University of Pennsylvania. Research reported in this publication was supported by the National Institute of General Medical Sciences of the National Institutes of Health under award number R35GM138201, the Defense Threat Reduction Agency (DTRA; HDTRA11810041 and HDTRA1-21-1-0014), and by Programma Operativo Nazionale (PON) Ricerca e Innovazione 2014-2020 ?Dottorati innovativi con caratterizzazione industriale?. Publisher Copyright: © 2022 American Chemical Society
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