Health and Life Sciences Department, Université Paris Saclay, French Alternative Energies and Atomic Energy Commission (CEA), CEA Saclay, Bat 152, 91191 Gif sur Yvette, France.
Institute for Research in Immunology and Cancer, Department of Biochemistry and Molecular Medicine, Université de Montréal, Montréal, Québec H3T 1J4, Canada.
J Med Chem. 2022 Sep 22;65(18):12084-12094. doi: 10.1021/acs.jmedchem.2c00786. Epub 2022 Sep 5.
The melanocortin 4 receptor (MC4R) plays a role in energy homeostasis and represents a target for treating energy balance disorders. For decades, synthetic ligands have been derived from MC4R endogenous agonists and antagonists, such as setmelanotide used to treat rare forms of genetic obesity. Recently, animal venoms have demonstrated their capacity to provide melanocortin ligands with toxins from a scorpion and a spider. Here, we described a cone snail toxin, N-CTX-Ltg1a, with a nanomolar affinity for hMC4R but unrelated to any known toxins or melanocortin ligands. We then derived from the conotoxin the linear peptide HT1-0, a competitive antagonist of , , and β-arrestin2 pathways with a low nanomolar affinity for hMC4R. Similar to endogenous ligands, HT1-0 needs hydrophobic and basic residues to bind hMC4R. Altogether, it represents the first venom-derived peptide of high affinity on MC4R and paves the way for the development of new MC4R antagonists.
黑皮质素 4 受体 (MC4R) 在能量平衡中发挥作用，是治疗能量平衡紊乱的靶点。几十年来，合成配体一直是从 MC4R 内源性激动剂和拮抗剂衍生而来的，例如用于治疗罕见遗传性肥胖症的 setmelanotide。最近，动物毒液已证明其具有提供黑皮质素配体的能力，这些配体来自蝎子和蜘蛛的毒素。在这里，我们描述了一种芋螺毒素，N-CTX-Ltg1a，对 hMC4R 的亲和力为纳摩尔级，但与任何已知的毒素或黑皮质素配体无关。然后，我们从该芋螺毒素衍生出线性肽 HT1-0，它是一种竞争性拮抗剂，对 ， 和β-arrestin2 途径具有低纳摩尔级亲和力，对 hMC4R 的亲和力为纳摩尔级。与内源性配体类似，HT1-0 需要疏水性和碱性残基来结合 hMC4R。总的来说，它代表了第一个对 MC4R 具有高亲和力的毒液衍生肽，为开发新的 MC4R 拮抗剂铺平了道路。
