A multi-targeting drug design strategy for identifying potent anti-SARS-CoV-2 inhibitors

被引：48

作者：

Ren, Peng-xuan ^{[1
,2
]}

Shang, Wei-juan ^{[3
]}

Yin, Wan-chao ^{[4
]}

Ge, Huan ^{[5
]}

Wang, Lin ^{[1
,2
]}

Zhang, Xiang-lei ^{[1
,2
]}

Li, Bing-qian ^{[1
,2
,6
]}

Li, Hong-lin ^{[5
]}

Xu, Ye-chun ^{[4
,7
]}

Xu, Eric H. ^{[4
,7
]}

Jiang, Hua-liang ^{[1
,2
,4
,7
]}

Zhu, Li-li ^{[5
]}

Zhang, Lei-ke ^{[3
]}

Bai, Fang ^{[1
,2
]}

机构：

[1] ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai 201210, Peoples R China

[2] ShanghaiTech Univ, Shanghai Inst Adv Immunochem Studies, Shanghai 201210, Peoples R China

[3] Chinese Acad Sci, Ctr Biosafety Mega Sci, Wuhan Inst Virol, State Key Lab Virol, Wuhan 430071, Peoples R China

[4] Chinese Acad Sci, Shanghai Inst Mat Med, CAS Key Lab Receptor Res, Shanghai 201203, Peoples R China

[5] East China Univ Sci & Technol, Sch Pharm, Shanghai Key Lab Drug Design, State Key Lab Bioreactor Engn, Shanghai 200237, Peoples R China

[6] Imperial Coll London, Dept Chem, London, England

[7] Univ Chinese Acad Sci, Beijing 100049, Peoples R China

来源：

ACTA PHARMACOLOGICA SINICA | 2022年 / 43卷 / 02期

基金：

中国国家自然科学基金; 上海市科技启明星计划;

关键词：

SARS-CoV-2; inhibitors; RdRp; host ribosome; Virus RNA; STRUCTURAL BASIS; SARS-CORONAVIRUS; REPLICATION; SARS-COV-2; MECHANISMS; LYCORINE; IDENTIFICATION; COVID-19; EMETINE; PROTEIN;

D O I：

10.1038/s41401-021-00668-7

中图分类号：

O6 [化学];

学科分类号：

0703 ;

摘要：

The COVID-19, caused by SARS-CoV-2, is threatening public health, and there is no effective treatment. In this study, we have implemented a multi-targeted anti-viral drug design strategy to discover highly potent SARS-CoV-2 inhibitors, which simultaneously act on the host ribosome, viral RNA as well as RNA-dependent RNA polymerases, and nucleocapsid protein of the virus, to impair viral translation, frameshifting, replication, and assembly. Driven by this strategy, three alkaloids, including lycorine, emetine, and cephaeline, were discovered to inhibit SARS-CoV-2 with EC50 values of low nanomolar levels potently. The findings in this work demonstrate the feasibility of this multi-targeting drug design strategy and provide a rationale for designing more potent anti-virus drugs.

引用

页码：483 / 493

页数：11

共 65 条

[1]

Akinboye E. S., 2011, Open Natural Products Journal, V4, P8, DOI 10.2174/1874848101104010008

[2] Potential use of RNA-dependent RNA polymerase (RdRp) inhibitors against SARS-CoV2 infection [J].

Allen, Charles N. S. ;

Arjona, Sterling P. ;

Santerre, Maryline ;

Sawaya, Bassel E. .

ALL LIFE, 2020, 13 (01) :608-614

[3] Novel Antiviral Activities of Obatoclax, Emetine, Niclosamide, Brequinar, and Homoharringtonine [J].

Andersen, Petter, I ;

Krpina, Klara ;

Ianevski, Aleksandr ;

Shtaida, Nastassia ;

Jo, Eunji ;

Yang, Jaewon ;

Koit, Sandra ;

Tenson, Tanel ;

Hukkanen, Veijo ;

Anthonsen, Marit W. ;

Bjoras, Magnar ;

Evander, Magnus ;

Windisch, Marc P. ;

Zusinaite, Eva ;

Kainov, Denis E. .

VIRUSES-BASEL, 2019, 11 (10)

[4] Structures of the human and Drosophila 80S ribosome [J].

Anger, Andreas M. ;

Armache, Jean-Paul ;

Berninghausen, Otto ;

Habeck, Michael ;

Subklewe, Marion ;

Wilson, Daniel N. ;

Beckmann, Roland .

NATURE, 2013, 497 (7447) :80-+

[5] Multiscale perspectives of virus entry via endocytosis [J].

Barrow, Eric ;

Nicola, Anthony V. ;

Liu, Jin .

VIROLOGY JOURNAL, 2013, 10

[6] UniProt: a worldwide hub of protein knowledge [J].

Bateman, Alex ;

Martin, Maria-Jesus ;

Orchard, Sandra ;

Magrane, Michele ;

Alpi, Emanuele ;

Bely, Benoit ;

Bingley, Mark ;

Britto, Ramona ;

Bursteinas, Borisas ;

Busiello, Gianluca ;

Bye-A-Jee, Hema ;

Da Silva, Alan ;

De Giorgi, Maurizio ;

Dogan, Tunca ;

Castro, Leyla Garcia ;

Garmiri, Penelope ;

Georghiou, George ;

Gonzales, Daniel ;

Gonzales, Leonardo ;

Hatton-Ellis, Emma ;

Ignatchenko, Alexandr ;

Ishtiaq, Rizwan ;

Jokinen, Petteri ;

Joshi, Vishal ;

Jyothi, Dushyanth ;

Lopez, Rodrigo ;

Luo, Jie ;

Lussi, Yvonne ;

MacDougall, Alistair ;

Madeira, Fabio ;

Mahmoudy, Mahdi ;

Menchi, Manuela ;

Nightingale, Andrew ;

Onwubiko, Joseph ;

Palka, Barbara ;

Pichler, Klemens ;

Pundir, Sangya ;

Qi, Guoying ;

Raj, Shriya ;

Renaux, Alexandre ;

Lopez, Milagros Rodriguez ;

Saidi, Rabie ;

Sawford, Tony ;

Shypitsyna, Aleksandra ;

Speretta, Elena ;

Turner, Edward ;

Tyagi, Nidhi ;

Vasudev, Preethi ;

Volynkin, Vladimir ;

Wardell, Tony .

NUCLEIC ACIDS RESEARCH, 2019, 47 (D1) :D506-D515

[7] Coronavirus genome structure and replication [J].

Brian, DA ;

Baric, RS .

CORONAVIRUS REPLICATION AND REVERSE GENETICS, 2005, 287 :1-30

[8] Infectability of Human BrainSphere Neurons Suggests Neurotropism of SARS-CoV-2 [J].

Bullen, C. Korin ;

Hogberg, Helena T. ;

Bahadirli-Talbott, Asli ;

Bishai, William R. ;

Hartung, Thomas ;

Keuthan, Casey ;

Looney, Monika M. ;

Pekosz, Andrew ;

Romero, J. Carolina ;

Sille, Fenna C. M. ;

Um, Peter ;

Smirnova, Lena .

ALTEX-ALTERNATIVES TO ANIMAL EXPERIMENTATION, 2020, 37 (04) :665-671

[9] Multiple biological functions and pharmacological effects of lycorine [J].

Cao ZhiFei ;

Yang Ping ;

Zhou QuanSheng .

SCIENCE CHINA-CHEMISTRY, 2013, 56 (10) :1382-1391

[10] A proposed role for the SARS-CoV-2 nucleocapsid protein in the formation and regulation of biomolecular condensates [J].

Cascarina, Sean M. ;

Ross, Eric D. .

FASEB JOURNAL, 2020, 34 (08) :9832-9842

← 1 2 3 4 5 6 7 →