Abstract
Peptide drugs have been used in the treatment of multiple pathologies. During peptide discovery, it is crucially important to be able to map the potential sites of cleavages of the proteases. This knowledge is used to later chemically modify the peptide drug to adapt it for the therapeutic use, making peptide stable against individual proteases or in complex medias. In some other cases it needed to make it specifically unstable for some proteases, as peptides could be used as a system to target delivery drugs on specific tissues or cells. The information about proteases, their sites of cleavages and substrates are widely spread across publications and collected in databases such as MEROPS. Therefore, it is possible to develop models to improve the understanding of the potential peptide drug proteolysis. We propose a new workflow to derive protease specificity rules and predict the potential scissile bonds in peptides for individual proteases. WebMetabase stores the information from experimental or external sources in a chemically aware database where each peptide and site of cleavage is represented as a sequence of structural blocks connected by amide bonds and characterized by its physicochemical properties described by Volsurf descriptors. Thus, this methodology could be applied in the case of non-standard amino acid. A frequency analysis can be performed in WebMetabase to discover the most frequent cleavage sites. These results were used to train several models using logistic regression, support vector machine and ensemble tree classifiers to map cleavage sites for several human proteases from four different families (serine, cysteine, aspartic and matrix metalloproteases). Finally, we compared the predictive performance of the developed models with other available public tools PROSPERous and SitePrediction.
Highlights
Proteolytic enzymes play critical role in many processes including cell proliferation, immune response, cell death and others [1]
Since the system used to derive the cleavage site appearance rules could be linked to the software assisted metabolite structure elucidation based on MS data, the database is automatically enriched with the new experiments
Predicting possible sites of cleavage for individual proteases is an important task to be completed during drug-design process of peptide therapeutics to improve their stability and availably as a promising drug
Summary
Proteolytic enzymes play critical role in many processes including cell proliferation, immune response, cell death and others [1]. Protease cleavage of peptides is directed by short amino acid motifs, from two to eight amino acids around the scissile bond (site of cleavage, SoC) [4]. This specific amino acid sequence is recognized by the active site of a given protease, but the efficiency of a proteolytic activity is related to the structural properties of the SoC. Kazanov et al [5] studied the structural preferences of cleavage sited by mapping 200 proteolytic events to the CutDB [6]. It has been shown that the following additional factors to the peptide sequences influence on a cleavage such as unfolding events, allosteric effects, solvent accessibility, secondary structure of the sequence etc. It has been shown that the following additional factors to the peptide sequences influence on a cleavage such as unfolding events, allosteric effects, solvent accessibility, secondary structure of the sequence etc. [7]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
