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利用肽噬菌体展示技术研究白细胞介素-17A上的热点及其对药物发现的意义。

Utilization of peptide phage display to investigate hotspots on IL-17A and what it means for drug discovery.

作者信息

Ting Joey P, Tung Frances, Antonysamy Stephen, Wasserman Stephen, Jones Spencer B, Zhang Feiyu F, Espada Alfonso, Broughton Howard, Chalmers Michael J, Woodman Michael E, Bina Holly A, Dodge Jeffrey A, Benach Jordi, Zhang Aiping, Groshong Christopher, Manglicmot Danalyn, Russell Marijane, Afshar Sepideh

机构信息

Department of protein Engineering, Eli Lilly Biotechnology Center, San Diego, California, United States of America.

Department of structural Biology, Discovery Chemistry Research and Technologies, Lilly Biotechnology Center, Eli Lilly and Company, San Diego, California, United States of America.

出版信息

PLoS One. 2018 Jan 12;13(1):e0190850. doi: 10.1371/journal.pone.0190850. eCollection 2018.

DOI:10.1371/journal.pone.0190850
PMID:29329326
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC5766103/
Abstract

To date, IL-17A antibodies remain the only therapeutic approach to correct the abnormal activation of the IL-17A/IL-17R signaling complex. Why is it that despite the remarkable success of IL-17 antibodies, there is no small molecule antagonist of IL-17A in the clinic? Here we offer a unique approach to address this question. In order to understand the interaction of IL-17A with its receptor, we combined peptide discovery using phage display with HDX, crystallography, and functional assays to map and characterize hot regions that contribute to most of the energetics of the IL-17A/IL-17R interaction. These functional maps are proposed to serve as a guide to aid in the development of small molecules that bind to IL-17A and block its interaction with IL-17RA.

摘要

迄今为止，IL-17A抗体仍然是纠正IL-17A/IL-17R信号复合物异常激活的唯一治疗方法。尽管IL-17抗体取得了显著成功，但临床上为何没有IL-17A的小分子拮抗剂呢？在此，我们提供了一种独特的方法来解决这个问题。为了了解IL-17A与其受体的相互作用，我们将噬菌体展示的肽发现与氢氘交换、晶体学和功能测定相结合，以绘制和表征对IL-17A/IL-17R相互作用的大部分能量学有贡献的热点区域。这些功能图谱被认为可作为指导，以帮助开发与IL-17A结合并阻断其与IL-17RA相互作用的小分子。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b46d/5766103/e5558b4e72ad/pone.0190850.g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b46d/5766103/6a8427f57dfd/pone.0190850.g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b46d/5766103/563025a6354a/pone.0190850.g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b46d/5766103/d9f81ca8afe5/pone.0190850.g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b46d/5766103/ebf0c54056fe/pone.0190850.g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b46d/5766103/f20e0ab200fd/pone.0190850.g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b46d/5766103/e5558b4e72ad/pone.0190850.g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b46d/5766103/6a8427f57dfd/pone.0190850.g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b46d/5766103/563025a6354a/pone.0190850.g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b46d/5766103/d9f81ca8afe5/pone.0190850.g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b46d/5766103/ebf0c54056fe/pone.0190850.g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b46d/5766103/f20e0ab200fd/pone.0190850.g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b46d/5766103/e5558b4e72ad/pone.0190850.g006.jpg

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