RESUMO
Many systemically effective drugs such as cyclosporin A are ineffective topically because of their poor penetration into skin. To surmount this problem, we conjugated a heptamer of arginine to cyclosporin A through a pH-sensitive linker to produce R7-CsA. In contrast to unmodified cyclosporin A, which fails to penetrate skin, topically applied R7-CsA was efficiently transported into cells in mouse and human skin. R7-CsA reached dermal T lymphocytes and inhibited cutaneous inflammation. These data establish a general strategy for enhancing delivery of poorly absorbed drugs across tissue barriers and provide a new topical approach to the treatment of inflammatory skin disorders.
Assuntos
Arginina/análogos & derivados , Arginina/farmacocinética , Ciclosporinas/farmacocinética , Inflamação/prevenção & controle , Pró-Fármacos/farmacocinética , Pele/metabolismo , Administração Tópica , Animais , Arginina/síntese química , Arginina/uso terapêutico , Transporte Biológico , Biotinilação , Ciclosporina/administração & dosagem , Ciclosporina/química , Ciclosporinas/administração & dosagem , Ciclosporinas/síntese química , Ciclosporinas/uso terapêutico , Humanos , Interleucina-2/biossíntese , Ionomicina/farmacologia , Células Jurkat , Camundongos , Camundongos Endogâmicos BALB C , Estrutura Molecular , Pró-Fármacos/síntese química , Pró-Fármacos/uso terapêutico , Pele/citologia , Absorção Cutânea , Acetato de Tetradecanoilforbol/farmacologiaRESUMO
[formula: see text] A unique class of simplified phorbol ester analogues is described for the first time. A highly efficient retro-annelation sequence was developed in order to remove the five-membered ring from the phorbol diterpene core, allowing access to BCD ring analogues of the phorbol esters. The binding of these analogues to protein kinase C (PKC) and the truncated peptide eta PKC-C1B (eta PKC-CRD2) is also reported.