Unveiling Neanderthal and Denisovan Peptides with Antibiotic Potential through Molecular De-Extinction

Resurrected peptides from Neanderthals and Denisovans exhibit antibiotic effects.

Advancements in computational and experimental techniques have unlocked a fascinating realm of 'encrypted' peptides within the proteomes of ancient humans. Researchers, driven by the concept of 'molecular de-extinction,' have explored these peptides in Neanderthal proteins, revealing a promising source of medicinal molecules, including peptides with antibiotic properties. This pioneering work

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, led by César de la Fuente from the University of Pennsylvania, introduces a novel approach that bridges the gap between ancient biomolecules and modern healthcare solutions.

The idea of resurrecting molecules from the past to address contemporary challenges has evoked comparisons to "Jurassic Park," albeit with a focus on small molecules. Unlike attempts to revive entire extinct organisms, this method carries fewer ethical concerns while offering significant technological potential. De la Fuente's team had previously devised an algorithm to uncover 'encrypted' peptides, fragments detached from larger proteins, within the human proteome. These peptides, despite their enigmatic roles, could play essential functions in the immune system.

Machine learning tools helped to identify archaic peptides that could have beneficial medicinal properties

Encouraged by their findings within the modern human proteome, the researchers expanded their investigation to the proteomes of Neanderthals and Denisovans, our closest relatives. Despite the limited sequence data available, the team identified 69 promising peptides, with six demonstrating antibiotic activity against various pathogens in mouse models. While these antibiotics are not notably potent, the evidence of in vivo activity and moderate toxicity presents a promising foundation for further exploration.

An intriguing aspect of these active peptides lies in their sequence dissimilarity from known antimicrobial peptides. The ancient peptides exhibit higher levels of polar, acidic, and aromatic amino acids, contrasting with lower levels of basic residues. This unique distribution could signify evolutionary pressures that shaped these proteins in the past. Nonetheless, caution is warranted due to the limited sample size, and further research is needed to explore the full range of peptides that existed in extinct organisms.

One notable observation is the apparent preference of de-extinct peptides to target the inner membrane of Gram-negative bacteria. This contrasts with modern encrypted peptides that often target the outer membrane. This observation, albeit preliminary, has significant implications for designing drugs against antibiotic-resistant microorganisms. The results are particularly promising, with one de-extinct peptide showing remarkable efficacy against skin infections in mice, comparable to contemporary solutions.

In the face of the growing crisis of antibiotic resistance, the discovery of peptides with potential antibiotic properties from Neanderthal proteins offers a hopeful avenue for novel drug development. As de-extinct peptides present a compelling strategy for uncovering new antibiotics, this study marks a pivotal starting point for further exploration and innovation in the realm of ancient biomolecules and their contribution to modern medicine.

1. Maasch, J. R. M. A., Torres, M. D. T., Melo, M. C. R., & de la Fuente-Nunez, C. (2023). Molecular de-extinction of ancient antimicrobial peptides enabled by machine learning. Cell Host & Microbe, 31(8), 1260-1274.e6. https://doi.org/10.1016/j.chom.2023.07.001