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Peer-reviewedCC BY 4.0Biomolecules

From Amphibian Extracts to Focused Libraries: An Algorithm-Based Strategy to Uncover Potent Multi-Target Anti-Alzheimer Peptides

  • Álvaro José Rietmann1,2
  • Iván Sanchis1,2
  • Roque Spinelli1,2
  • Javier Alejandro López2,3
  • Álvaro S. Siano1,2
  1. 1Laboratorio de Péptidos Bioactivos, Departamento de Química Orgánica, Facultad de Bioquímica y Ciencias Biológicas, Universidad Nacional del Litoral, Santa Fe 3000, Argentina
  2. 2Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Godoy Cruz 2290, Ciudad Autónoma de Buenos Aires (CABA) 1425, Argentina
  3. 3Grupo de Estudios Sobre Anfibios, Laboratorio de Biodiversidad y Conservación de Tetrápodos, Instituto Nacional de Limnología (INALI: CONICET-UNL), Santa Fe 3000, Argentina
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Abstract

Alzheimer’s disease (AD) is a multifactorial neurodegenerative disorder, driving the search for multitarget-directed ligands (MTDLs) able to modulate multiple pathological pathways. Since amphibians represent a rich source of bioactive peptides, skin extracts from Scinax nasicus and Dendropsophus nanus, classified by sex, developmental stage, and season, were evaluated against key AD-related mechanisms, including cholinesterase inhibition, antioxidant activity, and Fe2+ chelation. Subsequently, a rational discovery workflow was implemented, integrating extract-level chemical characterization and bioactivity screening with the sequence identification of the main components and a novel in silico algorithm-based prioritization. This strategy, formalized through the Multi-Target Therapeutic Potential Score (MTTP-Score), served as a rational filter to produce a focused synthetic library, significantly minimizing experimental time and cost. Peptides derived from D. nanus (Dn) displayed the most promising multitarget candidates. Dn-7 combined sub-micromolar dual cholinesterase inhibition (IC50 = 0.32 and 1.2 µM for AChE and BChE, respectively) with highly efficient Fe2+ chelation (EC50 = 39 µM), representing the highest MTDL activity reported for an amphibian peptide. Dn-18 emerged as a moderate butyrylcholinesterase inhibitor with strong metal chelating capacity. Overall, this study establishes a pipeline for the rational discovery of peptide-based MTDL scaffolds for AD.

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Cite

BibTeXRIS
BibTeX
@article{rietmann2026from,
  title = {{From Amphibian Extracts to Focused Libraries: An Algorithm-Based Strategy to Uncover Potent Multi-Target Anti-Alzheimer Peptides}},
  author = {Álvaro José Rietmann and Iván Sanchis and Roque Spinelli and Javier Alejandro López and Álvaro S. Siano},
  journal = {Biomolecules},
  year = {2026},
  month = oct,
  doi = {10.3390/biom16101458},
  url = {https://www.mdpi.com/2218-273X/16/10/1458},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - From Amphibian Extracts to Focused Libraries: An Algorithm-Based Strategy to Uncover Potent Multi-Target Anti-Alzheimer Peptides
AU  - Álvaro José Rietmann
AU  - Iván Sanchis
AU  - Roque Spinelli
AU  - Javier Alejandro López
AU  - Álvaro S. Siano
PY  - 2026
DA  - 2026/10/01
JO  - Biomolecules
DO  - 10.3390/biom16101458
UR  - https://www.mdpi.com/2218-273X/16/10/1458
AB  - Alzheimer’s disease (AD) is a multifactorial neurodegenerative disorder, driving the search for multitarget-directed ligands (MTDLs) able to modulate multiple pathological pathways. Since amphibians represent a rich source of bioactive peptides, skin extracts from Scinax nasicus and Dendropsophus nanus, classified by sex, developmental stage, and season, were evaluated against key AD-related mechanisms, including cholinesterase inhibition, antioxidant activity, and Fe2+ chelation. Subsequently, a rational discovery workflow was implemented, integrating extract-level chemical characterization and bioactivity screening with the sequence identification of the main components and a novel in silico algorithm-based prioritization. This strategy, formalized through the Multi-Target Therapeutic Potential Score (MTTP-Score), served as a rational filter to produce a focused synthetic library, significantly minimizing experimental time and cost. Peptides derived from D. nanus (Dn) displayed the most promising multitarget candidates. Dn-7 combined sub-micromolar dual cholinesterase inhibition (IC50 = 0.32 and 1.2 µM for AChE and BChE, respectively) with highly efficient Fe2+ chelation (EC50 = 39 µM), representing the highest MTDL activity reported for an amphibian peptide. Dn-18 emerged as a moderate butyrylcholinesterase inhibitor with strong metal chelating capacity. Overall, this study establishes a pipeline for the rational discovery of peptide-based MTDL scaffolds for AD.
SN  - 2218-273X
ER  -