Biomimetic Peptide Engineering Laboratory, Department of Chemistry, Indian Institute of Technology, Ropar, Punjab, India.
J Pept Sci. 2023 Sep;29(9):e3489. doi: 10.1002/psc.3489. Epub 2023 Apr 13.
Controlling certain diseases using peptide drugs has remarkably increased in the past two decades. In this regard, a generic formulation is an upfront solution to fulfill market demands. Ganirelix, a leading peptide active pharmaceutical ingredient (API) primarily used as a gonadotropin-releasing hormone antagonist (GnRH), has established a potential market value worldwide. But its generic formulation mandates detailed impurity profiles from a synthetic source and contemplates the sameness of a reference-listed drug (RLD). Post-chemical synthesis and processing of Ganirelix, some commercial sources have revealed two new potential impurities among many known, which show the deletion of an ethyl group from the hArg(Et) residue at the sixth and eighth positions, named des-ethyl-Ganirelix. These impurities are unprecedented in traditional peptide chemistry, and such monoethylated-hArg building blocks are not easily accessible commercially to synthesize these two impurities. Here, we have outlined the synthesis, purification, and enantiomeric purity characterization of the amino acids and their incorporation in the Ganirelix peptide sequence to synthesize these potential peptide impurities. This methodology will enable the convenient synthesis of side-chain substituted Arg and hArg derivatives in peptide drug discovery platforms.
在过去的二十年中，使用肽类药物控制某些疾病的方法显著增加。在这方面，通用配方是满足市场需求的一种前置解决方案。加尼瑞克是一种主要用作促性腺激素释放激素拮抗剂 (GnRH) 的肽类原料药 (API)，已在全球范围内建立了潜在的市场价值。但是，其通用配方需要从合成来源获得详细的杂质概况，并考虑到参比制剂药物 (RLD) 的一致性。加尼瑞克在化学合成和后处理后，一些商业来源在许多已知的杂质中发现了两种新的潜在杂质，它们显示出第六位和第八位的 hArg(Et) 残基上的乙基基团缺失，命名为去乙基加尼瑞克。这些杂质在传统的肽化学中是前所未有的，而且这种单乙基化的 hArg 砌块在商业上不容易获得，无法用于合成这两种杂质。在这里，我们概述了这些氨基酸的合成、纯化和对映体纯度特征，以及它们在加尼瑞克肽序列中的掺入，以合成这些潜在的肽类杂质。这种方法将使侧链取代的 Arg 和 hArg 衍生物在肽类药物发现平台中的方便合成成为可能。
