Preprint Article Version 1 This version is not peer-reviewed

Synthesis of Temporin-SHa Retro Analogs with Lysine Addition / Substitution and Antibiotic Conjugation to Enhance Antibacterial, Antifungal, and Anticancer Activities

Shahzad Nazir
ORCID logo ,
Arif Iftikhar Khan
* ,
Rukesh Maharjan
* ORCID logo ,
Sadiq Noor Khan
,
Muhammad Adnan Akram
,
Marc Maresca
* ORCID logo ,
Farooq-Ahmad Khan
ORCID logo ,
Farzana Shaheen
* ORCID logo
Version 1 : Received: 6 November 2024 / Approved: 7 November 2024 / Online: 7 November 2024 (07:23:19 CET)

How to cite: Nazir, S.; Khan, A. I.; Maharjan, R.; Khan, S. N.; Akram, M. A.; Maresca, M.; Khan, F.-A.; Shaheen, F. Synthesis of Temporin-SHa Retro Analogs with Lysine Addition / Substitution and Antibiotic Conjugation to Enhance Antibacterial, Antifungal, and Anticancer Activities. Preprints 2024, 2024110510. https://doi.org/10.20944/preprints202411.0510.v1 Nazir, S.; Khan, A. I.; Maharjan, R.; Khan, S. N.; Akram, M. A.; Maresca, M.; Khan, F.-A.; Shaheen, F. Synthesis of Temporin-SHa Retro Analogs with Lysine Addition / Substitution and Antibiotic Conjugation to Enhance Antibacterial, Antifungal, and Anticancer Activities. Preprints 2024, 2024110510. https://doi.org/10.20944/preprints202411.0510.v1

Abstract

In the face of rising threat of resistant pathogens, antimicrobial peptides (AMPs) offer a viable alternative to the current challenge due to their broad-spectrum activity. This study focuses on enhancing the efficacy of temporin-SHa derived NST-2 peptide (1), which is known for its antimicrobial and anticancer activities. We synthesized new analogs of 1 using three strategies, i.e. retro analog preparation, lysine addition/substitution, and levofloxacin conjugation. Analogs were tested in term of antibacterial, antifungal, and anticancer activities. Analog 2 corresponding to retro analog of NST-2 was found more active but also more hemolytic, reducing its selectivity index and therapeutic potential. Addition of lysine (in analog 3) and lysine substitution (in analog 7) reduced the hemolytic effect resulting in safer peptides. Conjugation with levofloxacin on lysine side chain (in analogs 4 and 5) decreased the hemolytic effect but unfortunately also the antimicrobial and anticancer activities of the analogs. Oppositely, conjugation with levofloxacin at the N-terminus of the peptide via β-alanine linker (in analogs 6 and 8) increased their antimicrobial and anticancer activity but also their hemolytic effect, resulting in less safe/selective analogs. In conclusion, lysine addition/substitution and levofloxacin conjugation, at least at the N-terminal position through β-alanine linker, were found to enhance the therapeutic potential of retro analogs of NST-2 whereas other modifications decreased the activity or increased the toxicity of the peptides.

Keywords

Temporin SHa; levofloxacin; antimicrobial peptides; AMPs; antibacterial; antifungal; anticancer

Subject

Biology and Life Sciences, Biology and Biotechnology

Copyright: This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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