“PROTAC” modified dihydroquinolizinones (DHQs) that cause degradation of PAPD-5 and inhibition of hepatitis A virus and hepatitis B virus, in vitro,Bioorganic & Medicinal Chemistry Letters

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“PROTAC” modified dihydroquinolizinones (DHQs) that cause degradation of PAPD-5 and inhibition of hepatitis A virus and hepatitis B virus, in vitro
Bioorganic & Medicinal Chemistry Letters ( IF 2.5 ) Pub Date : 2024-02-29 , DOI: 10.1016/j.bmcl.2024.129680
You Li ₁ , Nicky Hwang ₂ , Andrew Snedeker ₂ , Stanley M Lemon ₁ , Daisy Noe ₂ , Liren Sun ₂ , Jason A Clement ₂ , Tianlun Zhou ₂ , Liudi Tang ₂ , Timothy Block ₂ , Yanming Du ₂

Affiliation

Dihydroquinolizinones (DHQs) that inhibit cellular polyadenylating polymerases 5 and 7 (PAPD5 & 7), such as RG7834, have been shown to inhibit both hepatitis A (HAV) and hepatitis B virus (HBV) and . In this report, we describe RG7834-based proteolysis-targeting chimeras (PROTACs), such as compound , (6S)-9-((1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-21-oxo-3,6,9,12,15,18-hexaoxa-22-azapentacosan-25-yl)oxy)-6-isopropyl-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-]isoquinoline-3-carboxylic acid. The PROTAC DHQs described here inhibited an HAV reporter virus with an IC of 277 nM. Although the PROTAC DHQs were also inhibitory to HBV, their activities were substantially less potent against HBV , being in the 10 to 20 µM range, based on the reduction of HBsAg and HBV mRNA levels. Importantly, unlike RG7834, the incubation of cells with PROTAC DHQ resulted in the degradation of PAPD5, as expected for a PROTAC compound, but curiously not PAPD7. PAPD5 polypeptide degradation was prevented when a proteasome inhibitor, epoxomicin, was used, indicating that proteasome mediated proteolysis was associated with the observed activities of . Taken together, these data show that is the first example of a PROTAC that suppresses both HAV and HBV that is based on a small molecule warhead. The possibility that it has mechanisms that differ from its parent compound, RG7834, and has clinical value, is discussed.

中文翻译：

“PROTAC”修饰的二氢喹嗪酮 (DHQ) 在体外可降解 PAPD-5 并抑制甲型肝炎病毒和乙型肝炎病毒

抑制细胞聚腺苷酸聚合酶 5 和 7 (PAPD5 & 7) 的二氢喹啉酮 (DHQ)，例如 RG7834，已被证明可以抑制甲型肝炎 (HAV) 和乙型肝炎病毒 (HBV) 和。在本报告中，我们描述了基于 RG7834 的蛋白水解靶向嵌合体 (PROTAC)，例如化合物 , (6S)-9-((1-((2-(2,6-dioxopiperidin-3-yl)-1,3 -二氧代异二氢吲哚-4-基)氨基)-21-氧代-3,6,9,12,15,18-六氧杂-22-氮杂五二烷-25-基)氧基)-6-异丙基-10-甲氧基-2-氧代-6,7-二氢-2H-吡啶并[2,1-]异喹啉-3-羧酸。此处描述的 PROTAC DHQ 可抑制 HAV 报告病毒，IC 值为 277 nM。尽管 PROTAC DHQ 也能抑制 HBV，但基于 HBsAg 和 HBV mRNA 水平的降低，它们对 HBV 的活性显着降低，在 10 至 20 µM 范围内。重要的是，与 RG7834 不同，细胞与 PROTAC DHQ 一起孵育会导致 PAPD5 降解，正如 PROTAC 化合物所预期的那样，但奇怪的是 PAPD7 却不会。当使用蛋白酶体抑制剂环氧霉素时，PAPD5 多肽的降解被阻止，表明蛋白酶体介导的蛋白水解与观察到的活性相关。总而言之，这些数据表明，这是基于小分子弹头的同时抑制 HAV 和 HBV 的 PROTAC 的第一个例子。讨论了它具有与其母体化合物 RG7834 不同的机制并具有临床价值的可能性。

更新日期：2024-02-29

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