Biological activities of [Thr 2]sarafotoxin-b, a synthetic analogue of sarafotoxin-b

Abstract

The 21 amino acid sarafotoxins (SRTX) c and d/e as well as endothelin-3 (ET-3) are known to be less toxic and weaker pharmacologically than the other isopeptides SRTX-a, SRTX-b and ET-1. Since SRTX-c, SRTX-d/e and ET-3 possess a Thr instead of a Ser at position 2, we investigated the possibility that this mutation could be responsible for the observed biological differences. Here we show that the synthetic [Thr 2]SRTX-b has indeed a lower vasoconstriction efficacy (≈35%) in the rabbit aorta, but it is nearly as potent as SRTX-b in toxicity tests and in influencing contraction of the rat uterus. Using monoclonal antibodies directed against the structurally related endothelin-1, we also show that the antigenicity of the analogue is comparable to that of SRTX-b, suggesting that the overall structure of the two peptides is similar, despite the substitution at position 2. We suggest that the Thr 2 substitution contributes to the lower activity of the ‘weak’ peptides in some systems; however, additional substitutions found in the ‘weak’ peptides of the ET/SRTX family most probably contribute to their low pharmacological activity.