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      The wasp venom antimicrobial peptide polybia‐CP and its synthetic derivatives display antiplasmodial and anticancer properties

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          Abstract

          The wasp venom‐derived antimicrobial peptide polybia‐CP has been previously shown to exhibit potent antimicrobial activity, but it is also highly toxic. Previously, using a physicochemical‐guided peptide design strategy, we reversed its toxicity while preserving and even enhancing its antibacterial properties. Here, we report on several additional unanticipated biological properties of polybia‐CP and derivatives, namely their ability to target Plasmodium sporozoites and cancer cells. We leverage a physicochemical‐guided approach to identify features that operate as functional hotspots making these peptides viable antiplasmodial and anticancer agents. Helical content and net positive charge are identified as key structural and physicochemical determinants for antiplasmodial activity. In addition to helicity and net charge, hydrophobicity‐related properties of polybia‐CP and derivatives were found to be equally critical to target cancer cells. We demonstrate that by tuning these physicochemical parameters, it is possible to design synthetic peptides with enhanced submicromolar antiplasmodial potency and micromolar anticancer activity. This study reveals novel and previously undescribed functions for Polybia‐CP and analogs. Additionally, we demonstrate that a physicochemical‐guided rational design strategy can be used for identifying functional hotspots in peptide molecules and for tuning structure–function to generate novel and potent new‐to‐nature therapies.

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          Most cited references 28

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          Pseudomonas aeruginosa: all roads lead to resistance.

          Pseudomonas aeruginosa is often resistant to multiple antibiotics and consequently has joined the ranks of 'superbugs' due to its enormous capacity to engender resistance. It demonstrates decreased susceptibility to most antibiotics due to low outer membrane permeability coupled to adaptive mechanisms and can readily achieve clinical resistance. Newer research, using mutant library screens, microarray technologies and mutation frequency analysis, has identified very large collections of genes (the resistome) that when mutated lead to resistance as well as new forms of adaptive resistance that can be triggered by antibiotics themselves, in in vivo growth conditions or complex adaptations such as biofilm growth or swarming motility. Copyright © 2011 Elsevier Ltd. All rights reserved.
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            Bacterial biofilm development as a multicellular adaptation: antibiotic resistance and new therapeutic strategies.

            Bacteria have evolved the ability to form multicellular, surface-adherent communities called biofilms that allow survival in hostile environments. In clinical settings, bacteria are exposed to various sources of stress, including antibiotics, nutrient limitation, anaerobiosis, heat shock, etc., which in turn trigger adaptive responses in bacterial cells. The combination of this and other defense mechanisms results in the formation of highly (adaptively) resistant multicellular structures that are recalcitrant to host immune clearance mechanisms and very difficult to eradicate with the currently available antimicrobial agents, which are generally developed for the eradication of free-swimming (planktonic) bacteria. However, novel strategies that specifically target the biofilm mode of growth have been recently described, thus providing the basis for future anti-biofilm therapy. Copyright © 2013 Elsevier Ltd. All rights reserved.
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              Antimicrobial Peptides for Therapeutic Applications: A Review

              Antimicrobial peptides (AMPs) have been considered as potential therapeutic sources of future antibiotics because of their broad-spectrum activities and different mechanisms of action compared to conventional antibiotics. Although AMPs possess considerable benefits as new generation antibiotics, their clinical and commercial development still have some limitations, such as potential toxicity, susceptibility to proteases, and high cost of peptide production. In order to overcome those obstacles, extensive efforts have been carried out. For instance, unusual amino acids or peptido-mimetics are introduced to avoid the proteolytic degradation and the design of short peptides retaining antimicrobial activities is proposed as a solution for the cost issue. In this review, we focus on small peptides, especially those with less than twelve amino acids, and provide an overview of the relationships between their three-dimensional structures and antimicrobial activities. The efforts to develop highly active AMPs with shorter sequences are also described.
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                Author and article information

                Contributors
                vani.junior@ufabc.edu.br
                cfuente@pennmedicine.upenn.edu , cfuente@upenn.edu
                Journal
                Bioeng Transl Med
                Bioeng Transl Med
                10.1002/(ISSN)2380-6761
                BTM2
                Bioengineering & Translational Medicine
                John Wiley & Sons, Inc. (Hoboken, USA )
                2380-6761
                05 June 2020
                September 2020
                : 5
                : 3 ( doiID: 10.1002/btm2.v5.3 )
                Affiliations
                [ 1 ] Machine Biology Group, Departments of Psychiatry and Microbiology, Institute for Biomedical Informatics, Institute for Translational Medicine and Therapeutics, Perelman School of Medicine, Penn Institute for Computational Science, and Department of Bioengineering University of Pennsylvania Philadelphia Pennsylvania USA
                [ 2 ] Centro de Ciências Naturais e Humanas Universidade Federal do ABC Santo André SP Brazil
                [ 3 ] Departamento de Bioquímica Universidade Federal de São Paulo São Paulo SP Brazil
                [ 4 ] Departamento de Biofísica Universidade Federal de São Paulo São Paulo SP Brazil
                Author notes
                [* ] Correspondence

                Vani X. Oliveira Jr, Centro de Ciências Naturais e Humanas, Universidade Federal do ABC, Santo André, SP, Brazil.

                Email: vani.junior@ 123456ufabc.edu.br

                Cesar de la Fuente‐Nunez, Machine Biology Group, Departments of Psychiatry and Microbiology, Institute for Biomedical Informatics, Institute for Translational Medicine and Therapeutics, Perelman School of Medicine, Penn Institute for Computational Science, and Department of Bioengineering, University of Pennsylvania, Philadelphia, PA 19104.

                Email: cfuente@ 123456pennmedicine.upenn.edu ; cfuente@ 123456upenn.edu

                Article
                BTM210167
                10.1002/btm2.10167
                7510464
                ba5e8669-4e04-4ac2-b3ad-27b226175f7d
                © 2020 The Authors. Bioengineering & Translational Medicine published by Wiley Periodicals, Inc. on behalf of The American Institute of Chemical Engineers.

                This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

                Page count
                Figures: 3, Tables: 0, Pages: 7, Words: 4839
                Product
                Funding
                Funded by: Fundação de Amparo à Pesquisa do Estado de São Paulo
                Award ID: #2014/12938‐6
                Funded by: Penn Mental Health AIDS Research Center of the University of Pennsylvania
                Funded by: Institute for Diabetes, Obesity, and Metabolism
                Categories
                Rapid Communication
                Rapid Communications
                Custom metadata
                2.0
                September 2020
                Converter:WILEY_ML3GV2_TO_JATSPMC version:5.9.1 mode:remove_FC converted:23.09.2020

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