Eaton William A
Laboratory of Chemical Physics, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, United States.
Front Mol Biosci. 2022 Nov 3;9:1062346. doi: 10.3389/fmolb.2022.1062346. eCollection 2022.
I was fortunate to do my military service during the Vietnam era as a medical officer at the National Institutes of Health (NIH) in Bethesda, Maryland. My first research at NIH was concerned with making a variety of optical measurements on nucleic acid bases and proteins, including single crystal spectra in linearly polarized light and near infrared circular dichroism, interpreting the spectra using molecular orbital and crystal field theories. What I do now is drug discovery, a field at the opposite end of the scientific spectrum. This article gives a brief account of my transition from spectroscopy to sickle cell hemoglobin polymerization to protein folding to drug discovery for treating sickle cell disease. My lab recently developed a high throughput assay to screen the 12,657 compounds of the California Institute of Biomedical Research ReFrame drug repurposing library. This is a precious library because the compounds have either been FDA approved or have been tested in clinical trials. Since the 1970s numerous agents have been reported in the literature to inhibit HbS polymerization and/or sickling with only one successful drug, hydroxyurea, and another of dubious value, voxelotor, even though it has been approved by the FDA. Our screen has discovered 106 anti-sickling agents in the ReFrame compound library. We estimate that as many as 21 of these compounds could become oral drugs for treating sickle cell disease because they inhibit at concentrations typical of the free concentrations of oral drugs in human serum.
我很幸运在越南战争时期作为一名军医在美国国立卫生研究院（NIH）位于马里兰州贝塞斯达的分院服役。我在NIH的第一项研究是对核酸碱基和蛋白质进行各种光学测量，包括线性偏振光下的单晶光谱和近红外圆二色性，并使用分子轨道和晶体场理论解释光谱。我现在从事的是药物研发工作，这是科学领域的另一端。本文简要介绍了我从光谱学转向镰状细胞血红蛋白聚合、蛋白质折叠，再到治疗镰状细胞病的药物研发的历程。我的实验室最近开发了一种高通量检测方法，用于筛选加利福尼亚生物医学研究所ReFrame药物重新利用库中的12657种化合物。这是一个珍贵的库，因为这些化合物要么已获得美国食品药品监督管理局（FDA）批准，要么已在临床试验中进行过测试。自20世纪70年代以来，文献中报道了许多能够抑制镰状细胞血红蛋白（HbS）聚合和/或镰变的药物，但只有一种成功的药物——羟基脲，以及另一种价值存疑的药物——伐地那非（尽管它已获得FDA批准）。我们的筛选在ReFrame化合物库中发现了106种抗镰变药物。我们估计，这些化合物中多达21种可能会成为治疗镰状细胞病的口服药物，因为它们在人血清中口服药物的典型游离浓度下具有抑制作用。
