Prolyl 4-hydroxylase, a target enzyme for drug development. Design of suppressive agents and the in vitro effects of inhibitors and proinhibitors.
The hydrophilic compound pyridine 2,4-dicarboxylate (2,4-PDCA), designed as a mechanism-based competitive inhibitor of prolyl 4-hydroxylase, is efficiently excluded by the cytoplasmic membrane, but permeates the endoplasmic membrane via a 2,4-PDCA-selective translocator to reach its target enzyme in the intracisternal space. A lipophilic 2,4-PDCA-based proinhibitor, inactive with purified prolyl 4-hydroxylase, shows a cell system-dependent suppression of hydroxyprolyl formation, displaying a half-maximally inhibitory concentration very similar to the Ki of the parent compound. Apparently, cell-specific intracellular metabolic processing of the proinhibitor regenerates the active agent, 2,4-PDCA. The in vitro findings summarized here suggest that the 2,4-PDCA-mediated inhibition of prolyl 4-hydroxylase has a marked disruptive effect on the biosynthesis and deposition of collagen. This effect qualifies 2,4-PDCA and its derivatives as experimental fibrosuppressive compounds. However, to avoid catastrophic consequences in vivo, it is desirable to target the active agent to only the tissue that is compromised by excessive matrix formation. This requirement can be realized by the deliberate selection of an appropriate, 2,4-PDCA-based proinhibitor and by the deliberate selection of the route of proinhibitor administration.
Hanauske-Abel
H M
HM
Department of Pediatrics, New York Hospital-Cornell University Medical College, NY 10021.
D000818:Animals; D001667:Binding, Competitive; D003238:Connective Tissue / Q000502:physiology; D015195:Drug Design; D006801:Humans; D007700:Kinetics; D008103:Liver Cirrhosis / Q000517:prevention & control; D008954:Models, Biological; D011393:Procollagen-Proline Dioxygenase / Q000302:isolation & purification / Q000378:metabolism* / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology*
D011725:Pyridines; C055293:2,4-pyridinedicarboxylic acid; D011393:Procollagen-Proline Dioxygenase