<em>In vitro</em> and <em>in vivo</em> studies of topoisomers of a snake venom-derived peptide with anti-infective and antitumoral activity — ASN Events

In vitro and in vivo studies of topoisomers of a snake venom-derived peptide with anti-infective and antitumoral activity (#223)

Adam Carrera 1 , Sira Defaus 1 , Clara Pérez-Peinado 1 , Roberto Bello 2 , Daniel Sandín 2 , Marc Torrent 2 , Maria Ángeles Jiménez 3 , David Andreu 1
  1. Universitat Pompeu Fabra, Q5850017D, Barcelona, Spain
  2. Universitat Autonoma de Barcelona, Barcelona
  3. Instituto de Química Física Rocasolano , Madrid

To combat antimicrobial resistance (AMR), it is essential to have a good understanding of the infection mechanisms, particularly those concerning the interaction between anti-infective agents and pathogen targets. Within this context, antimicrobial peptides (AMPs) are emerging as promising therapeutic alternatives amid the pressing global issue of AMR. Their appeal stems from straightforward yet effective mechanisms of action, wide-ranging efficacy, adaptability for structural modifications through versatile peptide engineering techniques, and cost-effective production.

Ctn[15-34]1,2, a segment at the C-terminal of crotalicidin (Ctn), a cathelicidin sourced from a South American pit viper, stands as a candidate antimicrobial and antitumoral peptide. Notably, it exhibits significantly greater stability in human serum compared to its parent Ctn. This work delves into a series of topoisomers of both Ctn and Ctn[15-34], including their retro, enantio, and retroenantio versions to uncover the structural prerequisites for their activity3. Remarkably, all topoisomers demonstrate comparable in vitro activity to their cognate sequences against gram-negative bacteria and tumor cells, albeit slightly elevated toxicity toward normal cells. Furthermore, their heightened stability in human fluids enhances their prospects for future exploration. Hence Ctn[15-34] and Ctn retroenantio, the best in vitro performers, were selected for an in vivo efficacy evaluation in a murine model of Acinetobacter baumannii systemic infection. Unexpectedly, all animals treated with retroenantio peptide succumbed within 8 h. In contrast, for Ctn[15-34] divergent survival outcomes between genders were found, females outlasting males by ~ 1 day.

  1. Falcao, C.B.; Pérez-Peinado, C.; De La Torre, B.G.; Mayol, X.; Zamora-Carreras, H.; Jiménez, M.Á.; Rádis-Baptista, G.; Andreu, D. Structural Dissection of Crotalicidin, a Rattlesnake Venom Cathelicidin, Retrieves a Fragment with Antimicrobial and Antitumor Activity. J. Med. Chem. 2015, 58, 8553–8563
  2. Pérez‐Peinado, C.; Dias, S.A.; Mendonça, D.A.; Castanho, M.A.R.B.; Veiga, A.S.; Andreu, D. Structural determinants conferring unusual long life in human serum to rattlesnake‐derived antimicrobial peptide Ctn[15‐34]. J. Pept. Sci. 2019, 25, e3195
  3. Carrera-Aubesart, A.; Defaus, S.; Pérez-Peinado, C.; Sandín, D.; Torrent, M.; Jiménez, M.Á.; Andreu, D. Examining Topoisomers of a Snake-Venom-Derived Peptide for Improved Antimicrobial and Antitumoral Properties. Biomedicines 2022, 10, 2110.
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