Re-evaluation of Cyclic Peptide Binding to Neurotensin Receptor 1 by Shifting the Peptide Register during Synthesis.

IF 3.5 3区医学 Q2 CHEMISTRY, MEDICINAL ACS Medicinal Chemistry Letters Pub Date : 2024-12-19 eCollection Date: 2025-01-09 DOI:10.1021/acsmedchemlett.4c00542

Lazarus Andrew de Zhang, Mengjie Liu, Daniel J Scott, David K Chalmers

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Abstract

The head-to-tail cyclic peptide cyclo[Arg-Lys-Pro-Tyr-Tle-Leu] (peptide 1, where Tle is l-tert-Leu) has previously been reported to bind to neurotensin receptor 1 (NTS1) (pKi = 5.97). Upon seeking to reproduce this finding, we found that peptide 1 did not have a measurable affinity for NTS1. However, a semipurified preparation of peptide 1 appeared to bind to NTS1 with pKi = 5.83 ± 0.25 SEM. Resynthesis of peptide 1 using a shifted peptide register gave linear and cyclic forms of peptide 1 that were both unable to bind to NTS1. We observe that the previously reported activity of peptide 1 may be due to the presence of high affinity linear contaminants. Approximately 3% contamination with the linear variant would explain the apparent binding of the semipure peptide 1 sample. From this study, we propose that shifting the peptide register during synthesis as a strategy to minimize the presence of potent precursor contaminants.

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在合成过程中，通过改变肽区来重新评估环肽与神经紧张素受体1的结合。

头部到尾部的环状肽cyclo[arg - lys - pro - tir -Tle- leu]（肽1，其中Tle是l-tert-Leu）先前被报道与神经紧张素受体1 （NTS1）结合（pKi = 5.97）。在试图重现这一发现时，我们发现肽1对NTS1没有可测量的亲和力。然而，半纯化的肽1似乎与NTS1结合，pKi = 5.83±0.25 SEM。利用移位的肽寄存器重新合成肽1得到线性和环状形式的肽1，它们都不能与NTS1结合。我们观察到先前报道的肽1的活性可能是由于高亲和力线性污染物的存在。大约3%的线性变异污染可以解释半纯肽1样品的明显结合。从这项研究中，我们建议在合成过程中转移肽寄存器作为一种策略，以尽量减少强效前体污染物的存在。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

ACS Medicinal Chemistry Letters CHEMISTRY, MEDICINAL-

CiteScore

7.30

自引率

2.40%

发文量

328

审稿时长

1 months

期刊介绍： ACS Medicinal Chemistry Letters is interested in receiving manuscripts that discuss various aspects of medicinal chemistry. The journal will publish studies that pertain to a broad range of subject matter, including compound design and optimization, biological evaluation, drug delivery, imaging agents, and pharmacology of both small and large bioactive molecules. Specific areas include but are not limited to: Identification, synthesis, and optimization of lead biologically active molecules and drugs (small molecules and biologics) Biological characterization of new molecular entities in the context of drug discovery Computational, cheminformatics, and structural studies for the identification or SAR analysis of bioactive molecules, ligands and their targets, etc. Novel and improved methodologies, including radiation biochemistry, with broad application to medicinal chemistry Discovery technologies for biologically active molecules from both synthetic and natural (plant and other) sources Pharmacokinetic/pharmacodynamic studies that address mechanisms underlying drug disposition and response Pharmacogenetic and pharmacogenomic studies used to enhance drug design and the translation of medicinal chemistry into the clinic Mechanistic drug metabolism and regulation of metabolic enzyme gene expression Chemistry patents relevant to the medicinal chemistry field.

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