Sequence-based prediction of the intrinsic solubility of peptides containing non-natural amino acids

Marc Oeller, Ryan J. D. Kang, Hannah L. Bolt, Ana L. Gomes dos Santos, Annika Langborg Weinmann, Antonios Nikitidis, Pavol Zlatoidsky, Wu Su, Werngard Czechtizky, Leonardo De Maria, Pietro Sormanni () and Michele Vendruscolo ()
Additional contact information
Marc Oeller: University of Cambridge
Ryan J. D. Kang: University of Cambridge
Hannah L. Bolt: Hit Discovery, Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca
Ana L. Gomes dos Santos: Advanced Drug Delivery, Pharmaceutical Sciences, BioPharmaceuticals R&D, AstraZeneca
Annika Langborg Weinmann: Early Chemical Development, Pharmaceutical Sciences, BioPharmaceuticals R&D, AstraZeneca
Antonios Nikitidis: Medicinal Chemistry, Research and Early Development, Respiratory and Immunology, BioPharmaceuticals R&D, AstraZeneca
Pavol Zlatoidsky: Medicinal Chemistry, Research and Early Development, Respiratory and Immunology, BioPharmaceuticals R&D, AstraZeneca
Wu Su: Medicinal Chemistry, Research and Early Development, Respiratory and Immunology, BioPharmaceuticals R&D, AstraZeneca
Werngard Czechtizky: Medicinal Chemistry, Research and Early Development, Respiratory and Immunology, BioPharmaceuticals R&D, AstraZeneca
Leonardo De Maria: Medicinal Chemistry, Research and Early Development, Respiratory and Immunology, BioPharmaceuticals R&D, AstraZeneca
Pietro Sormanni: University of Cambridge
Michele Vendruscolo: University of Cambridge

Nature Communications, 2023, vol. 14, issue 1, 1-12

Abstract: Abstract Non-natural amino acids are increasingly used as building blocks in the development of peptide-based drugs as they expand the available chemical space to tailor function, half-life and other key properties. However, while the chemical space of modified amino acids (mAAs) such as residues containing post-translational modifications (PTMs) is potentially vast, experimental methods for measuring the developability properties of mAA-containing peptides are expensive and time consuming. To facilitate developability programs through computational methods, we present CamSol-PTM, a method that enables the fast and reliable sequence-based prediction of the intrinsic solubility of mAA-containing peptides in aqueous solution at room temperature. From a computational screening of 50,000 mAA-containing variants of three peptides, we selected five different small-size mAAs for a total number of 37 peptide variants for experimental validation. We demonstrate the accuracy of the predictions by comparing the calculated and experimental solubility values. Our results indicate that the computational screening of mAA-containing peptides can extend by over four orders of magnitude the ability to explore the solubility chemical space of peptides and confirm that our method can accurately assess the solubility of peptides containing mAAs. This method is available as a web server at https://www-cohsoftware.ch.cam.ac.uk/index.php/camsolptm .

Date: 2023
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DOI: 10.1038/s41467-023-42940-w

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