Synthesis of Temporin-SHa Retro Analogs with Lysine Addition/Substitution and Antibiotic Conjugation to Enhance Antibacterial, Antifungal, and Anticancer Activities
In the face of rising the 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 (<b>1</b>), which is known f...
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2024-12-01
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| Series: | Antibiotics |
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| author | Shahzad Nazir Arif Iftikhar Khan Rukesh Maharjan Sadiq Noor Khan Muhammad Adnan Akram Marc Maresca Farooq-Ahmad Khan Farzana Shaheen |
| author_facet | Shahzad Nazir Arif Iftikhar Khan Rukesh Maharjan Sadiq Noor Khan Muhammad Adnan Akram Marc Maresca Farooq-Ahmad Khan Farzana Shaheen |
| author_sort | Shahzad Nazir |
| collection | DOAJ |
| description | In the face of rising the 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 (<b>1</b>), which is known for its antimicrobial and anticancer activities. We synthesized new analogs of <b>1</b> using three strategies, i.e., retro analog preparation, lysine addition/substitution, and levofloxacin conjugation. Analogs were tested in terms of their antibacterial, antifungal, and anticancer activities. Analog <b>2,</b> corresponding to retro analog of NST-2, was found to be more active but also more hemolytic, reducing its selectivity index and therapeutic potential. The addition of lysine (in analog <b>3</b>) and lysine substitution (in analog <b>7</b>) reduced the hemolytic effect resulting in safer peptides. Conjugation with levofloxacin on the lysine side chain (in analogs <b>4</b> and <b>5</b>) 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 the β-alanine linker (in analogs <b>6</b> and <b>8</b>) 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 the 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. |
| format | Article |
| id | doaj-art-e898ddd1cc4f41f08372acf371b99df9 |
| institution | Kabale University |
| issn | 2079-6382 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Antibiotics |
| spelling | doaj-art-e898ddd1cc4f41f08372acf371b99df92024-12-27T14:06:23ZengMDPI AGAntibiotics2079-63822024-12-011312121310.3390/antibiotics13121213Synthesis of Temporin-SHa Retro Analogs with Lysine Addition/Substitution and Antibiotic Conjugation to Enhance Antibacterial, Antifungal, and Anticancer ActivitiesShahzad Nazir0Arif Iftikhar Khan1Rukesh Maharjan2Sadiq Noor Khan3Muhammad Adnan Akram4Marc Maresca5Farooq-Ahmad Khan6Farzana Shaheen7Third World Center for Science and Technology, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, PakistanThird World Center for Science and Technology, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, PakistanThird World Center for Science and Technology, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, PakistanThird World Center for Science and Technology, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, PakistanThird World Center for Science and Technology, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, PakistanAix Marseille Univ, CNRS, Centrale Med, ISM2, 13013 Marseille, FranceThird World Center for Science and Technology, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, PakistanThird World Center for Science and Technology, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, PakistanIn the face of rising the 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 (<b>1</b>), which is known for its antimicrobial and anticancer activities. We synthesized new analogs of <b>1</b> using three strategies, i.e., retro analog preparation, lysine addition/substitution, and levofloxacin conjugation. Analogs were tested in terms of their antibacterial, antifungal, and anticancer activities. Analog <b>2,</b> corresponding to retro analog of NST-2, was found to be more active but also more hemolytic, reducing its selectivity index and therapeutic potential. The addition of lysine (in analog <b>3</b>) and lysine substitution (in analog <b>7</b>) reduced the hemolytic effect resulting in safer peptides. Conjugation with levofloxacin on the lysine side chain (in analogs <b>4</b> and <b>5</b>) 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 the β-alanine linker (in analogs <b>6</b> and <b>8</b>) 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 the 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.https://www.mdpi.com/2079-6382/13/12/1213temporin-SHalevofloxacinantimicrobial peptidesAMPsantibacterialantifungal |
| spellingShingle | Shahzad Nazir Arif Iftikhar Khan Rukesh Maharjan Sadiq Noor Khan Muhammad Adnan Akram Marc Maresca Farooq-Ahmad Khan Farzana Shaheen Synthesis of Temporin-SHa Retro Analogs with Lysine Addition/Substitution and Antibiotic Conjugation to Enhance Antibacterial, Antifungal, and Anticancer Activities Antibiotics temporin-SHa levofloxacin antimicrobial peptides AMPs antibacterial antifungal |
| title | Synthesis of Temporin-SHa Retro Analogs with Lysine Addition/Substitution and Antibiotic Conjugation to Enhance Antibacterial, Antifungal, and Anticancer Activities |
| title_full | Synthesis of Temporin-SHa Retro Analogs with Lysine Addition/Substitution and Antibiotic Conjugation to Enhance Antibacterial, Antifungal, and Anticancer Activities |
| title_fullStr | Synthesis of Temporin-SHa Retro Analogs with Lysine Addition/Substitution and Antibiotic Conjugation to Enhance Antibacterial, Antifungal, and Anticancer Activities |
| title_full_unstemmed | Synthesis of Temporin-SHa Retro Analogs with Lysine Addition/Substitution and Antibiotic Conjugation to Enhance Antibacterial, Antifungal, and Anticancer Activities |
| title_short | Synthesis of Temporin-SHa Retro Analogs with Lysine Addition/Substitution and Antibiotic Conjugation to Enhance Antibacterial, Antifungal, and Anticancer Activities |
| title_sort | synthesis of temporin sha retro analogs with lysine addition substitution and antibiotic conjugation to enhance antibacterial antifungal and anticancer activities |
| topic | temporin-SHa levofloxacin antimicrobial peptides AMPs antibacterial antifungal |
| url | https://www.mdpi.com/2079-6382/13/12/1213 |
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