Development of highly potent vasoactive compounds.

Maxadilan(Maxa)是一种有效的、持久的血管扩张剂，是由Lerner从食血沙蝇Lutzmyia long gipalpis(利什曼病的媒介)的唾液腺裂解物中分离出来的。Maxa由61个氨基酸组成，带有两个二硫键。最近，MAXA被发现是PACAP 1型受体(PAC1)的激动剂，尽管PACAP和MaxA之间没有显著的序列相似性。PACAPs属于神经肽的一个大家族，通过跨越G蛋白偶联受体的成员发挥作用。探索GPCRs的识别特性对于阐明其功能和药物开发具有特别重要的意义。为了开发PAC1的激动剂和拮抗剂，采用改进的合成工艺，用高效的SPPS合成了MaxA及其二硫键异构体和各种相关的多肽，如中间、N端和C端片段以及中间区缺失的MaxA，经过纯化和鉴定后，得到的多肽被用于不同的生物检测，包括利用大鼠脑膜的PAC 1结合实验和最近发展的黑素载体技术，以阐明识别PAC1的结构要求，特别是抗肿瘤作用。结果表明，MaxA的中段和第一个二硫键不是识别所必需的。中间区域缺失的MaxA片段对PAC1有拮抗作用。

Maxadilan (Maxa) is a potent and persistent vasodilator, which has been isolated from the salivary gland lysates of the blood feeding sand fly Lutzomyia longipalpis (a vector of leishmaniasis) by Lerner. Maxa consists of 61 amino acids with two disulfide linages. More recently, Maxa was found to be an agonist of the PACAP type 1 receptor (PAC1) although there is no significant sequence similarity between PACAPs and Maxa. PACAPs belong to a large family of neuropeptides that function through members spanning G-protein-coupled receptors. Exploring the recognition characteristics of GPCRs is particular important for the elucidation of their functions and development of pharmaceuticals. To develop agonists and antagonists against PAC1 , Maxa with its disulfide isomers and various related poptides such as middle, N- and C-terminal fragments as well as middle-region deleted Maxa have been prepared by highly efficient SPPS with improved synthesis protocols, After purification and characterization the peptides obtained were used in different bioassays that include a PAC 1 binding assay using rat brain membranes and the recent developed melanophore technology to elucidate the structure requirements for PAC1 recognition, especially anatgonistic actions. The results indicated that the middle section of Maxa and the first disulfide linkage are not essential for recognition. An antagonistic action to PAC1 is observed for the middle-region deleted Maxa fragment.