SAR STUDIES OF A TOXIC PEPTIDE

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Recently, a group of peptides from the venom of Trimeresurus wagleri, or Wagler's pit viper, have been purified and characterized in terms of their lethality to mice. Little is known concerning the molecular mechanism underlying the action of this class of peptides known as the waglerins. However, preliminary data indicate the following actions of one of the more potent waglerins, peptide I: 1. a "curare-like" action on the nicotinic acetylcholine receptor of rat skeletal muscle; 2. suppression of spontaneous, but not stimulus-evoked, quantal release of transmitter at the rat neuromuscular junction; 3. enhanced "rundown" of end-plate currents during repetitive nerve stimulation; 4. suppression of voltage-activated sodium and potassium currents in neurons from mouse brain. The present research proposal is designed to confirm these preliminary findings and validate the longstanding hypothesis that the venom of T. wagleri is neurotoxic. In addition, this work will enable a test of the hypothesis that the structure of a single polypeptide can be equi-toxic to several functional processes. Finally, experiments are proposed to explore the structure-activity relations (SAR) involved in the action of the purified waglerins, synthetic analogues, or fragments thereof. To meet these objectives, conventional electrophysiological recording will be used to explore the concentration-dependent effects of 7 pure waglerin peptides on pre- and postsynaptic functions of the neuromuscular junction of the mouse Triangularis sterni muscle. In addition, patch voltage-clamp techniques will be employed to explore the molecular basis of the interaction of these peptides with voltage-gated ion channels in murine brain cells. It is anticipated that such studies will lead to new toxins with which to explore the function of excitable cells as well as to new therapeutic agents to control neuronal function.