A hnRNPA2B1 agonist effectively inhibits HBV and SARS-CoV-2 omicron<i>in vivo</i>

Zuo, Daming; Chen, Yu; Cai, Jian‐Piao; Yuan, Hao-Yang; Wu, Junqi; Yin, Yue; Xie, Jingzhong; Lin, Jingmin; Luo, Jia; Feng, Yun; Ge, Longjiao; Zhou, Jia; Quinn, Ronald J.; Zhao, Sanjun; Tong, Xing; Jin, Dong-Yan; Yuan, Shuofeng; Dai, Shao‐Xing; Xu, Min

doi:10.1093/procel/pwac027

Cited by 5 publications

(4 citation statements)

References 45 publications

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“…1, б). Выбор этих карманов основан на изучении взаимодействия hnNPA2B1 с лигандом PAC-5 [13] и анализ структуры белка с помощью веб-сервера CASTp (рис. 1, б).…”

Section: Discussionunclassified

“…Согласно рассчитанному значению энергии связывания (ΔG) доксициклина и иринотекана с hnRNPA2B1, наиболее энергетически выгодное связывание происходит в карманах P0 и P4 (рис. 2), что также согласуется с исследованием [13].…”

Section: Discussionunclassified

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Heterogeneous nuclear ribonucleoprotein A2B1 (hnRNPA2B1) as a pathogenetically significant drug target for oncology therapy (molecular docking of irinotecan and doxycycline)

Волкова,

Шитяков,

Кравцов

2023

Nauchno-Prakticheskii Zhurnal «Patogenez»

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Актуальность. В последние годы гиперэкспрессия и накопление гетерогенного ядерного рибонкулеопротеина А2В1 (hnRNPA2B1) в новообразованиях рассматривается как новая типовая реакция, развивающаяся в ходе злокачественной прогрессии, а сам hnRNPA2B1 становится патогенетически значимой мишенью для противоопухолевых препаратов. Целью нашего исследования стало теоретическое моделирование in silico методом молекулярного докинга взаимодействий противоракового препарата иринотекана и антибиотика тетрациклинового ряда доксициклина с белком hnRNPA2B1. Результаты проведённых докингов указывают на ещё один механизм дезактивации hnRNPA2B1 за счет связывания лигандов с белком вместо молекул РНК. Среди наиболее вероятных карманов (P0–P4) наилучшее сродство наблюдалось в карманах P0 и P4, принадлежащих к доменам RRM1 и RRM2 соответственно. Оказалось, что сродство иринотекана (ΔG = –10,36 ккал/моль) выше, чем сродство доксициклина (ΔG = –8,20 ккал/моль). Полученное значение энергии связывания доксициклина указывает на образование комплекса hnRNPA2B1–доксициклин, что делает дальнейшее рассмотрение доксициклина как таргетного противоопухолевого препарата перспективным. Заключение. Рассчитанные значения энергии связывания указывают на фармакологически значимое образование комплексов hnRNPA2B1–иринотекан и hnRNPA2B1–доксициклин, что указывает на ещё один плейотропный противоопухолевый эффект этих препаратов. Context. In recent years, overexpression and accumulation of heterogeneous nuclear ribonculoprotein A2B1 (hnRNPA2B1) in neoplasms has been considered as a new typical reaction on cancer progression. Therefore, hnRNPA2B1 is a pathogenetically significant target for antitumor drugs. The aim of our study was the theoretical modeling in silico of the interactions of the anti-cancer drug irinotecan and the tetracycline antibiotic doxycycline with the hnRNPA2B1 protein. Results. The affinity of doxycycline and irinotecan to hnRNP A2B1 was calculated by molecular docking method. According to the results, affinity of irinotecan (ΔG = –10.36 kcal/mol) is higher than the affinity of doxycycline (ΔG = –8.20 kcal/mol). However, the value of the binding energy of doxycycline indicates the formation of the hnRNPA2B1 – doxycycline complex, which makes further studies of doxycycline as an anticancer drug potentially interesting. Conclusion. The binding energies (ΔG) of irinotecan and doxycycline to the target RNA-binding protein hnRNPA2B1 obtained by molecular modeling were -10.36 kcal/mol and -8.20 kcal/mol respectively. The calculated binding energy values indicate the pharmacologically significant formation of hnRNPA2B1–irinotecan and hnRNPA2B1–doxycycline complexes, which indicates another anti-cancer pleotropic effect of these drugs.

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Section: Discussionunclassified

Heterogeneous nuclear ribonucleoprotein A2B1 (hnRNPA2B1) as a pathogenetically significant drug target for oncology therapy (molecular docking of irinotecan and doxycycline)

Волкова,

Шитяков,

Кравцов

2023

Nauchno-Prakticheskii Zhurnal «Patogenez»

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“…In fact, small molecule agonists of hnRNPA2B1, such as pac5, have already been developed and shown benefits in treating HBV and SARS-CoV-2 omicron infections. 525 Applying these developments to cancer therapy is a promising direction for future exploration.…”

Section: Innate Immune Pathways In Cancermentioning

confidence: 99%

Harnessing innate immune pathways for therapeutic advancement in cancer

Hu,

Sun,

Lin

et al. 2024

Sig Transduct Target Ther

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The innate immune pathway is receiving increasing attention in cancer therapy. This pathway is ubiquitous across various cell types, not only in innate immune cells but also in adaptive immune cells, tumor cells, and stromal cells. Agonists targeting the innate immune pathway have shown profound changes in the tumor microenvironment (TME) and improved tumor prognosis in preclinical studies. However, to date, the clinical success of drugs targeting the innate immune pathway remains limited. Interestingly, recent studies have shown that activation of the innate immune pathway can paradoxically promote tumor progression. The uncertainty surrounding the therapeutic effectiveness of targeted drugs for the innate immune pathway is a critical issue that needs immediate investigation. In this review, we observe that the role of the innate immune pathway demonstrates heterogeneity, linked to the tumor development stage, pathway status, and specific cell types. We propose that within the TME, the innate immune pathway exhibits multidimensional diversity. This diversity is fundamentally rooted in cellular heterogeneity and is manifested as a variety of signaling networks. The pro-tumor effect of innate immune pathway activation essentially reflects the suppression of classical pathways and the activation of potential pro-tumor alternative pathways. Refining our understanding of the tumor’s innate immune pathway network and employing appropriate targeting strategies can enhance our ability to harness the anti-tumor potential of the innate immune pathway and ultimately bridge the gap from preclinical to clinical application.

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“…The positive role of hnRNPs in viral RNA replication/transcription renders these proteins as broad-spectrum antiviral targets. A hnRNPA2B1 agonist has been demonstrated to effectively inhibit HBV and SARS-CoV-2 omicron in vivo ( Zuo et al, 2023 ).…”

Section: Regulation Of Rna Synthesismentioning

confidence: 99%

Classification, replication, and transcription of Nidovirales

Liao,

Wang,

Liao

et al. 2024

Front. Microbiol.

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Nidovirales is one order of RNA virus, with the largest single-stranded positive sense RNA genome enwrapped with membrane envelope. It comprises four families (Arterividae, Mesoniviridae, Roniviridae, and Coronaviridae) and has been circulating in humans and animals for almost one century, posing great threat to livestock and poultry，as well as to public health. Nidovirales shares similar life cycle: attachment to cell surface, entry, primary translation of replicases, viral RNA replication in cytoplasm, translation of viral proteins, virion assembly, budding, and release. The viral RNA synthesis is the critical step during infection, including genomic RNA (gRNA) replication and subgenomic mRNAs (sg mRNAs) transcription. gRNA replication requires the synthesis of a negative sense full-length RNA intermediate, while the sg mRNAs transcription involves the synthesis of a nested set of negative sense subgenomic intermediates by a discontinuous strategy. This RNA synthesis process is mediated by the viral replication/transcription complex (RTC), which consists of several enzymatic replicases derived from the polyprotein 1a and polyprotein 1ab and several cellular proteins. These replicases and host factors represent the optimal potential therapeutic targets. Hereby, we summarize the Nidovirales classification, associated diseases, “replication organelle,” replication and transcription mechanisms, as well as related regulatory factors.

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A hnRNPA2B1 agonist effectively inhibits HBV and SARS-CoV-2 omicronin vivo

Cited by 5 publications

References 45 publications

Heterogeneous nuclear ribonucleoprotein A2B1 (hnRNPA2B1) as a pathogenetically significant drug target for oncology therapy (molecular docking of irinotecan and doxycycline)

Heterogeneous nuclear ribonucleoprotein A2B1 (hnRNPA2B1) as a pathogenetically significant drug target for oncology therapy (molecular docking of irinotecan and doxycycline)

Harnessing innate immune pathways for therapeutic advancement in cancer

Classification, replication, and transcription of Nidovirales

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