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Estimating peptide half‐life in serum from tunable, sequence‐related physicochemical properties

2021Journal article Open access
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dc.contributor.authorCavaco, Marco
dc.contributor.authorValle, Javier
dc.contributor.authorFlores, Isabel
dc.contributor.authorAndreu, David
dc.contributor.authorCastanho, Miguel A. R. B.
dc.date.accessioned2021-03-19T16:23:16Z
dc.date.available2021-03-19T16:23:16Z
dc.date.issued2021
dc.description© 2021 The Authors. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of the American Society for Clinical Pharmacology and Therapeutics. This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial‐NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.pt_PT
dc.description.abstractProteolytic instability is a critical limitation for peptide-based products. Although significant efforts are devoted to stabilize sequences against proteases/peptidases in plasma/serum, such approaches tend to be rather empirical, unspecific, time-consuming, and frequently not cost-effective. A more rational and potentially rewarding alternative is to identify the chemical grounds of susceptibility to enzymatic degradation of peptides so that proteolytic resistance can be tuned by manipulation of key chemical properties. In this regard, we conducted a meta-analysis of literature published over the last decade reporting experimental data on the lifetimes of peptides exposed to proteolytic conditions. Our initial database contained 579 entries and was curated with regard to amino acid sequence, chemical modification, terminal half-life (t1/2 ) or other stability readouts, type of stability assay, and biological application of the study. Although the majority of entries in the database corresponded to (slightly or substantially) modified peptides, we chose to focus on unmodified ones, as we aimed to decipher intrinsic characteristics of peptide proteolytic susceptibility. Specifically, we developed a multivariable regression model to unravel those peptide properties with most impact on proteolytic stability and thus potential t1/2 predicting ability. Model validation was done by two different approaches. First, a library of peptides spanning a large interval of properties that modulate stability was synthesized and their t1/2 in human serum were experimentally determined. Second, the t1/2 of 21 selected peptides approved for clinical use or in clinical trials were recorded and matched with the model-estimated values. With both approaches, good correlation between experimental and predicted t1/2 data was observed.pt_PT
dc.description.sponsorshipThis research was supported by the Portuguese Fundação para a Ciência e a Tecnologia (FCT; grants PD/BD/128281/2017, PTDC/BBB- NAN/1578/2014, PTDC/BIA- VIR/29495/2017, UID/Multi/04349/2019, and PTDC/QUI- NUC/30147/2017), the Spanish Ministry of Economy and Innovation (MINECO, grants AGL2014- 52395- C2- 2- R and AGL2017- 84097- C2- 2- R, and Maria de Maeztu Program for Centers of Excellence); the European Union H2020- MSCA- RISE- 2014 program (grant no. 828774), and the “La Caixa” Banking Foundation (grant HR17- 00409)pt_PT
dc.description.versioninfo:eu-repo/semantics/publishedVersionpt_PT
dc.identifier.citationClin Transl Sci. 2021 Feb 28.pt_PT
dc.identifier.doi10.1111/cts.12985pt_PT
dc.identifier.eissn1752-8062
dc.identifier.issn1752-8054
dc.identifier.urihttp://hdl.handle.net/10451/46930
dc.language.isoengpt_PT
dc.peerreviewedyespt_PT
dc.publisherJohn Wiley & Sons, Inc.pt_PT
dc.relationPTDC/BBB‐NAN/1578/2014pt_PT
dc.relationTrans-BBB peptides for targeting brain metastasis
dc.relationPTDC/QUI‐NUC/30147/2017pt_PT
dc.relationCentre for Nuclear Sciences and Technologies
dc.relation.publisherversionhttps://ascpt.onlinelibrary.wiley.com/journal/17528062pt_PT
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/4.0/pt_PT
dc.titleEstimating peptide half‐life in serum from tunable, sequence‐related physicochemical propertiespt_PT
dc.typejournal article
dspace.entity.typePublication
oaire.awardTitleTrans-BBB peptides for targeting brain metastasis
oaire.awardTitleCentre for Nuclear Sciences and Technologies
oaire.awardURIinfo:eu-repo/grantAgreement/FCT//PD%2FBD%2F128281%2F2017/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/6817 - DCRRNI ID/UID%2FMulti%2F04349%2F2019/PT
oaire.citation.titleClinical and Translational Sciencept_PT
oaire.fundingStream6817 - DCRRNI ID
person.familyNameCavaco
person.familyNameCastanho
person.givenNameMarco
person.givenNameMiguel
person.identifier1069324
person.identifier.ciencia-id1412-63B8-7494
person.identifier.orcid0000-0002-0938-9038
person.identifier.orcid0000-0001-7891-7562
person.identifier.scopus-author-id56605575600
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.nameFundação para a Ciência e a Tecnologia
project.funder.nameFundação para a Ciência e a Tecnologia
rcaap.rightsopenAccesspt_PT
rcaap.typearticlept_PT
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