每周分子 | Molecule of the Week

Original ACS 美国化学会 ACS美国化学会 2022-07-01

收录于合集 #每周分子 110个

每周分子：EIDD-2801

Molecule of the Week: EIDD-2801

科学家们继续以惊人的速度开发潜在的疗法和疫苗来抗击新冠肺炎(COVID-19)。在最近的报告中, 来自北卡罗莱纳大学教堂山分校的Timothy O. Sheahan和Ralph S. Baric、埃默里大学的George Painter和来自范德比尔特大学和疾病控制与预防中心的同事们发现, 现有抗病毒前药显示出抗SARS-CoV-2病毒的前景。

作者的工作始于一种名为EIDD-1931(β-d-N⁴-羟基胞苷或4-尿苷肟)的广谱抗病毒化合物，Painter及其同事们在2010年代早期开始将它作为抗病毒药物进行研究(EIDD是艾莫利药物开发研究所的缩写)。该分子对老鼠和狗身上的SARS-CoV病毒(导致严重的急性和中东呼吸综合症)有很好的抑制作用，但对猴子却无效。

发现EIDD-1931中的羟基在猴子的胃中被磷酸化，并且不能到达感染的细胞，研究人员寻求一种阻止磷酸化的方法。他们用2-甲基丙酸酯化了EIDD-1931中的羟基，生成分子EIDD-2801[尿苷5'-(2-甲基丙酸)，4-肟]，这不仅阻止了磷酸化，而且使预期的前药更具脂溶性，口服更有效。血液中的酶水解EIDD-2801，释放活性物质EIDD-1931。

在EIDD-2801成功对抗SARS-CoV之后，研究人员将他们的注意力转向了新型冠状病毒。在4月，他们表示，EIDD-2801的施用是“抗SARS-CoV-2的强抗病毒药物......在原发性人类上皮细胞培养中，无细胞毒性。”

在该发现后，事情进展很快。科学家们在48小时内完成了EIDD-2801的新药申请; 美国食品药品监督管理局在7天内批准了该申请。埃默里大学的药物创新公司（埃默里大学的附属公司）(DRIVE)随后将EIDD-2801许可给Ridgeback Biotherapeutics (Miami, FL)用于人体研究。

Painter相信，EIDD-2801可以作为COVID-19和其他冠状病毒疾病的治疗药物，甚至更好地作为接触过冠状病毒的个人的预防药物。

EIDD-2801信息速览

CAS 登记号	2349386-89-4
SciFinder命名	Uridine, 4-oxime, 5′-(2-methylpropanoate)
分子式	C₁₃H₁₉N₃O₇
摩尔质量	329.31
外观	白色或灰白色固体
熔点	未报到
水溶性	≈2 g/L

EIDD-2801危害信息

GHS*分类：急性毒性，口服，分类4
H302-吞咽有害
GHS分类：皮肤腐蚀/刺激，分类2
H315-引起皮肤过敏
GHS分类：严重眼睛损伤/眼睛刺激，分类2A
H319 -引起严重的眼睛刺激
GHS分类：特定靶器官毒性，单次接触，呼吸道刺激，分类3
H335-可能引起呼吸道刺激

【关于每周分子】

自2001年以来，“每周分子”已成为广受欢迎的栏目。多数分子由读者推荐。每个结构都经由科学家审查，并以3-D和平面图像的形式显示，同时附有该分子简介。可以通过美国化学文摘社 (CAS) 提供的SciFinder中的CAS REGISTRY获取“每周分子”的更多信息。CAS REGISTRY中的每条物质信息都展示了物质的CAS登记号、索引名、通用名、商品名、书目信息等其他更多信息。发送邮件至motw@acs.org推荐您感兴趣的分子吧。

Scientists continue to develop potential treatments for and vaccines against COVID-19 at a breathtaking pace. Among the most recent reports, Timothy O. Sheahan and Ralph S. Baric at the University of North Carolina at Chapel Hill, George Painter at Emory University (Atlanta), and colleagues there and at Vanderbilt University (Nashville, TN) and the Centers for Disease Control and Prevention (Atlanta) found that an existing antiviral prodrug shows promise against the SARS-CoV-2 virus.

The authors’ work originated with a broad-spectrum antiviral compound called EIDD-1931 (β-d-N⁴-hydroxycytidine or uridine 4-oxime) that Painter and co-workers began to investigate in the early 2010s as a coronavirus treatment. (EIDD stands for the Emory Institute for Drug Development.) The molecule worked well against the SARS-CoV virus (which causes the severe acute and Middle East respiratory syndromes) in mice and dogs, but not monkeys.

Finding that the hydroxyl group in EIDD-1931 was being phosphorylated in monkeys’ stomachs and could not get to infected cells, the researchers sought a way to block phosphorylation. They esterified the hydroxyl group in EIDD-1931 with 2-methylpropanoic acid to produce the molecule EIDD-2801 [uridine 5′-(2-methylpropanoate), 4-oxime], which not only prevented phosphorylation, but also made the prospective prodrug more lipid-soluble and therefore more available orally. Enzymes in the bloodstream hydrolyze EIDD-2801 to liberate the active agent EIDD-1931.

Following on the success of EIDD-2801 against SARS-CoV, the researchers turned their attention to the novel coronavirus. In April, they were able to state that the administration of EIDD-2801 is “potently antiviral against SARS-CoV-2 . . . in primary human epithelial cell cultures without cytotoxicity.”

Things happened fast after that discovery. The scientists wrote the investigational new drug application for EIDD-2801 in 48 h; and the US Food and Drug Administration approved the application in a near-record 7 days. Drug Innovation Ventures at Emory (DRIVE), a spin-off from the university, then licensed EIDD-2801 to Ridgeback Biotherapeutics (Miami, FL) for human studies.

Painter believes that EIDD-2801 could work as a treatment for COVID-19 and other coronaviral diseases and, even better, as a prophylactic for individuals who have been exposed to a coronavirus.

EIDD-2801 fast facts

CAS Reg. No.	2349386-89-4
SciFinder nomenclature	Uridine, 4-oxime, 5′-(2-methylpropanoate)
Empirical formula	C₁₃H₁₉N₃O₇
Molar mass	329.31
Appearance	White to off-white solid
Melting point	Not reported
Water solubility	≈2 g/L

EIDD-2801 hazard information

Hazard class: Acute toxicity, oral, category 4
H302-Harmful if swallowed
Hazard class: Skin corrosion/irritation , category 2
H315-Causes skin irritation
Hazard class: Serious eye damage/eye irritation, category 2A
H319 -Causes serious eye irritation
Hazard class: Specific target organ toxicity, single exposure, respiratory tract irritation, category 3
H335-May cause respiratory irritation

About Molecule of the Week

MOTW has been a popular feature on ACS website since 2001. Many molecules are suggested by our website visitors. Every structure is reviewed by a scientist and displayed in 3-D and flat images with a brief description. Each week’s molecule also links to a sample record from the CAS REGISTRY, which is searched using SciFinder. Each record displays the registry number, index name and synonyms, bibliographic information, and more. Send us a molecule suggestion at motw@acs.org.

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