Lovelace Erica S, Armishaw Christopher J, Colgrave Michelle L, Wahlstrom Maria E, Alewood Paul F, Daly Norelle L, Craik David J
Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland 4072, Australia.
J Med Chem. 2006 Nov 2;49(22):6561-8. doi: 10.1021/jm060299h.
Conotoxins, disulfide-rich peptides from the venom of cone snails, have created much excitement over recent years due to their potency and specificity for ion channels and their therapeutic potential. One recently identified conotoxin, MrIA, a 13-residue member of the chi-conotoxin family, inhibits the human norepinephrine transporter (NET) and has potential applications in the treatment of pain. In the current study, we show that the beta-hairpin structure of native MrIA is retained in a synthetic cyclic version, as is biological activity at the NET. Furthermore, the cyclic version has increased resistance to trypsin digestion relative to the native peptide, an intriguing result because the cleavage site for the trypsin is not close to the cyclization site. The use of peptides as drugs is generally hampered by susceptibility to proteolysis, and so, the increase in enzymatic stability against trypsin observed in the current study may be useful in improving the therapeutic potential of MrIA. Furthermore, the structure reported here for cyclic MrIA represents a new topology among a growing number of circular disulfide-rich peptides.
芋螺毒素是从芋螺毒液中提取的富含二硫键的肽，近年来因其对离子通道的效力和特异性以及治疗潜力而备受关注。最近发现的一种芋螺毒素MrIA，是χ-芋螺毒素家族的一个由13个氨基酸残基组成的成员，它能抑制人类去甲肾上腺素转运体（NET），在疼痛治疗方面具有潜在应用价值。在本研究中，我们发现天然MrIA的β-发夹结构在合成的环化形式中得以保留，并且在NET上的生物活性也得以保留。此外，相对于天然肽，环化形式对胰蛋白酶消化的抗性增强，这一结果很有趣，因为胰蛋白酶的切割位点并不靠近环化位点。肽类作为药物通常会受到蛋白水解易感性的阻碍，因此，本研究中观察到的对胰蛋白酶的酶稳定性增加可能有助于提高MrIA的治疗潜力。此外，此处报道的环化MrIA的结构代表了在越来越多的富含二硫键的环状肽中的一种新拓扑结构。
