RESUMO
Small-molecule inhibition of extracellular proteins that activate membrane receptors has proven to be extremely challenging. Diversity-oriented synthesis and small-molecule microarrays enabled the discovery of robotnikinin, a small molecule that binds the extracellular Sonic hedgehog (Shh) protein and blocks Shh signaling in cell lines, human primary keratinocytes and a synthetic model of human skin. Shh pathway activity is rescued by small-molecule agonists of Smoothened, which functions immediately downstream of the Shh receptor Patched.
Assuntos
Proteínas Hedgehog/metabolismo , Lactamas/farmacologia , Lactonas/farmacologia , Transdução de Sinais/efeitos dos fármacos , Células 3T3 , Animais , Descoberta de Drogas , Humanos , Queratinócitos/efeitos dos fármacos , Queratinócitos/metabolismo , Lactamas/metabolismo , Lactonas/metabolismo , Camundongos , Receptores Patched , Receptores de Superfície Celular/genética , Receptores de Superfície Celular/metabolismoRESUMO
In this paper we describe a highly effective surface modification of SU-8 microparticles, the attachment of appropriate linkers for solid-supported synthesis, and the successful chemical modification of these particles via controlled multi-step organic synthesis leading to molecules attached in an unambiguous manner to the support surface.