On the Process of Discovering Leads That Target the Heparin-Binding Site of Neutrophil Elastase in the Sputum of Cystic Fibrosis Patients.
J Med Chem
; 62(11): 5501-5511, 2019 06 13.
Article
em En
| MEDLINE
| ID: mdl-31074986
ABSTRACT
Cystic fibrosis (CF) is a disease of dysregulated salt and fluid homeostasis that results in the massive accumulation of neutrophil elastase, resulting in lung degradation and death. The current CF therapy relies on inhaled deoxyribonuclease and hypertonic saline but does not address the elastolytic degradation of the lung. We reasoned that allosteric agents targeting the heparin-binding site of neutrophil elastase would offer a therapeutic paradigm. Screening a library of 60 nonsaccharide glycosaminoglycan mimetics (NSGMs) led to the discovery of 23 hits against neutrophil elastase. To identify a lead NSGM that works in sync with the current CF-relieving agents, we developed a rigorous protocol based on fundamental computational, biochemical, mechanistic, and adverse effect studies. The lead NSGM so identified neutralized neutrophil elastase present in the sputum of CF patients in the presence of deoxyribonuclease and high-salt conditions. Our work presents the process for discovering potent, small, synthetic, allosteric, anti-CF agents, while also identifying a novel lead for further studies in animal models of CF.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Escarro
/
Heparina
/
Elastase de Leucócito
/
Fibrose Cística
/
Descoberta de Drogas
/
Terapia de Alvo Molecular
Tipo de estudo:
Guideline
Limite:
Humans
Idioma:
En
Revista:
J Med Chem
Assunto da revista:
QUIMICA
Ano de publicação:
2019
Tipo de documento:
Article
País de afiliação:
Estados Unidos