STRUCTURAL BASIS OF RELAXIN ACTION

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While relaxin remains our main target, the goals have been extended to include the structure-function relations of other relaxin-like factors that generally consist of two small disulfide-linked chains. The enigma of relatively low activity of exogenous human relaxin in contrast to the noticeable activity of endogenous relaxin during pregnancy may find an explanation in the fact that RLF, until recently unknown (see progress report), is a relaxin-enhancing factor. We have now established a rigorous synthesis that allows us to synthesize all of these factors and their variants and in the next grant period we will examine in detail the physiological importance of these factors and their functional relation to relaxin. Surprising was the discovery that RLF receptors are particularly numerous on the human ovarian cancer cell line 2008 (ovarian cystadeno carcinoma) and we are therefore planing to synthesize an RLF-ricin-A-chain complex which could serve to specifically poison certain ovarian cancer cells in vivo. A similar relaxin-ricin-A complex has been successful at killing tumor cells in vitro and will be used to rapidly identify relaxin receptor- bearing cells. This in turn will be very useful for the identification of relaxin receptor-bearing tumors for receptor isolation which is also a major goal of this research. Relaxin and insulin are likely complementary in their action against diabetes, in particular the disastrous vascular consequences of the disease. Purportedly relaxin causes increased peripheral blood flow and thereby healing of trophic ulcerations and reversal of incipient gangrene in the extremities. We will synthesize relaxin, RLF, and derivatives of greater potency and biostability if possible. In light of the increasing population of diabetics and the aging of our population in general such compounds would be of consequence for a large number of patients.