期刊
JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL ANALYSIS
卷 211, 期 -, 页码 -出版社
ELSEVIER
DOI: 10.1016/j.jpba.2021.114518
关键词
Peptide; Metabolism; LC-HRMS; In vitro assay; Automatization; Inhalation
Inhalation of peptides offers the advantage of targeting lung tissue directly, but they are often quickly metabolized in the lungs. An assay workflow has been developed to study the half-life and metabolites of peptides in lung tissue, guiding early stage respiratory drug discovery projects through chemical modifications of peptide hits.
The inhalation of peptides comes with the advantage of directly targeting the lung as tissue of interest. However, peptides are often rapidly metabolized in lung tissue through proteolytic cleavage. We have developed an assay workflow to obtain half-life and metabolite ID data for peptides incubated with four proteases abundant in lungs of asthma and COPD patients. The assay system has been validated using 28 structurally diverse linear and cyclic peptides with a molecular weight between 708 and 5808 Da. Experimental conditions for incubation, sample preparation, chromatography, data acquisition and analysis are compatible with the required throughput in early stage peptide projects. Together with co-crystal structures and Ala scans, we are using the described assay workflow to guide the first chemical modifications of peptide hits in early respiratory drug discovery projects.
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