Automated high-throughput in vitro assays to identify metabolic hotspots and protease stability of structurally diverse, pharmacologically active peptides for inhalation.
J Pharm Biomed Anal
; 211: 114518, 2022 Mar 20.
Article
en En
| MEDLINE
| ID: mdl-35124452
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.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Péptido Hidrolasas
/
Péptidos
Límite:
Humans
Idioma:
En
Revista:
J Pharm Biomed Anal
Año:
2022
Tipo del documento:
Article
Pais de publicación:
Reino Unido