RESUMO
Targeting protein-protein interaction (PPI) is rapidly becoming an attractive alternative for drug development. While drug development commonly involves inhibiting a PPI, in this study, we show that stabilizing PPI may also be therapeutically beneficial. Junctional proteins Neph1 and ZO-1 and their interaction is an important determinant of the structural integrity of slit diaphragm, which is a critical component of kidney's filtration system. Since injury induces loss of this interaction, we hypothesized that strengthening this interaction may protect kidney's filtration barrier and preserve kidney function. In this study, Neph1-ZO-1 structural complex was screened for the presence of small druggable pockets formed from contributions from both proteins. One such pocket was identified and screened using a small molecule library. Isodesmosine (ISD) a rare naturally occurring amino acid and a biomarker for pulmonary arterial hypertension was selected as the best candidate and to establish the proof of concept, its ability to enhance Neph1-CD and ZO-1 binding was tested. Results from biochemical binding analysis showed that ISD enhanced Neph1 and ZO-1 interaction under in vitro and in vivo conditions. Importantly, ISD treated podocytes were resistant to injury-induced loss of transepithelial permeability. Finally, mouse and zebrafish studies show that ISD protects from injury-induced renal damage.
Assuntos
Isodesmosina/farmacologia , Proteínas de Membrana/metabolismo , Podócitos/efeitos dos fármacos , Proteína da Zônula de Oclusão-1/metabolismo , Animais , Células Cultivadas , Taxa de Filtração Glomerular/efeitos dos fármacos , Humanos , Rim/efeitos dos fármacos , Rim/metabolismo , Rim/fisiopatologia , Proteínas de Membrana/química , Proteínas de Membrana/genética , Camundongos , Simulação de Acoplamento Molecular , Podócitos/metabolismo , Ligação Proteica/efeitos dos fármacos , Domínios Proteicos , Peixe-Zebra , Proteína da Zônula de Oclusão-1/química , Proteína da Zônula de Oclusão-1/genéticaRESUMO
The tetrasubstituted pyridinium amino acids isodesmosine and desmosine are cross-linkers of elastin and are attractive biomarkers for the diagnosis of chronic obstructive pulmonary disease (COPD). In this study, the biomimetic total synthesis of isodesmosine and desmosine via a lanthanide-promoted Chichibabin pyridine synthesis using the corresponding aldehyde and amine hydrochloride is reported.
