A pan-coronavirus fusion inhibitor targeting the HR1 domain of human coronavirus spike

Science Advances
Shuai XiaLu Lu

Abstract

Continuously emerging highly pathogenic human coronaviruses (HCoVs) remain a major threat to human health, as illustrated in past SARS-CoV and MERS-CoV outbreaks. The development of a drug with broad-spectrum HCoV inhibitory activity would address this urgent unmet medical need. Although previous studies have suggested that the HR1 of HCoV spike (S) protein is an important target site for inhibition against specific HCoVs, whether this conserved region could serve as a target for the development of broad-spectrum pan-CoV inhibitor remains controversial. Here, we found that peptide OC43-HR2P, derived from the HR2 domain of HCoV-OC43, exhibited broad fusion inhibitory activity against multiple HCoVs. EK1, the optimized form of OC43-HR2P, showed substantially improved pan-CoV fusion inhibitory activity and pharmaceutical properties. Crystal structures indicated that EK1 can form a stable six-helix bundle structure with both short α-HCoV and long β-HCoV HR1s, further supporting the role of HR1 region as a viable pan-CoV target site.

References

Dec 1, 1987·Proceedings of the National Academy of Sciences of the United States of America·S Marqusee, R L Baldwin
Oct 11, 1994·Proceedings of the National Academy of Sciences of the United States of America·C T WildT J Matthews
Nov 1, 1995·Journal of Biomolecular NMR·F DelaglioA Bax
Jan 24, 1998·Journal of Biomolecular Structure & Dynamics·M Lu, P S Kim
Oct 12, 2000·Journal of Virology·S WatanabeY Kawaoka
Oct 2, 2002·Nature Biotechnology·Marielle CavroisWarner C Greene
Nov 1, 2003·Virology·Hélène Jacomy, Pierre J Talbot
May 20, 2004·Proceedings of the National Academy of Sciences of the United States of America·Berend Jan BoschPeter J M Rottier
Jun 25, 2004·Nucleic Acids Research·Todd J DolinskyNathan A Baker
Sep 24, 2004·Virology·Marielle CavroisWarner C Greene
Dec 2, 2004·Acta Crystallographica. Section D, Biological Crystallography·Paul Emsley, Kevin Cowtan
May 24, 2005·Clinical Infectious Diseases : an Official Publication of the Infectious Diseases Society of America·Susan S ChiuJ S M Peiris
Mar 14, 2007·Pediatric Pulmonology·Arne SimonOliver Schildgen
Feb 26, 2009·The Journal of Infectious Diseases·Geoffrey J GorseKristin L Nichol
Jul 8, 2009·Trends in Molecular Medicine·So-Young ChoiStefan Pöhlmann
Jan 9, 2010·Acta Crystallographica. Section D, Biological Crystallography·Vincent B ChenDavid C Richardson
Feb 4, 2010·Acta Crystallographica. Section D, Biological Crystallography·Paul D AdamsPeter H Zwart
Jan 23, 2013·The Pediatric Infectious Disease Journal·Andréanne JeanMakeda Semret
May 2, 2014·Nucleic Acids Research·Marco BiasiniTorsten Schwede

❮ Previous
Next ❯

Citations

Jan 31, 2020·Bioscience Trends·Hongzhou Lu
May 6, 2020·British Journal of Pharmacology·Hong ZhouXiao-Ming Meng
Jun 3, 2020·International Journal of Molecular Sciences·Xinling WangShibo Jiang
Jun 18, 2020·Drug Metabolism Reviews·Abu HazafaSaira Bano
May 18, 2020·The FEBS Journal·Alexander WlodawerMariusz Jaskolski
Aug 31, 2020·The Journal of Membrane Biology·Gourab Prasad Pattnaik, Hirak Chakraborty
Aug 26, 2020·Pathogens and Disease·Jitendra Singh Rathore, Chaitali Ghosh
Aug 28, 2020·Medicinal Research Reviews·Thanigaimalai PillaiyarMaheswaran Easwaran
Sep 10, 2020·PloS One·Lluc Farrera-SolerNicolas Winssinger
Oct 2, 2020·PloS One·Grijesh Jaiswal, Veerendra Kumar
Mar 24, 2020·Indian Journal of Pharmacology·Manisha PrajapatBikash Medhi
May 15, 2020·AAPS PharmSciTech·Junqiang YanHua Fan
Jun 24, 2020·Biochemistry. Biokhimii︠a︡·O P Zhirnov
Jul 28, 2020·International Journal of Molecular Sciences·Alessandra FierabracciPaolo Rossi
Feb 13, 2020·Cellular & Molecular Immunology·Shuai XiaLu Lu
Jul 16, 2020·Chinese Medicine·Shahid HussainXing-Xing Fan
Jun 7, 2019·Emerging Microbes & Infections·Jiuyang XuLinqi Zhang
May 12, 2020·Frontiers in Microbiology·Longping V TseRalph S Baric
Aug 14, 2020·International Journal of Molecular Sciences·Rolando CannalireVincenzo Summa
Oct 10, 2020·European Journal of Clinical Microbiology & Infectious Diseases : Official Publication of the European Society of Clinical Microbiology·Yue-Peng JiangCheng-Ping Wen
Oct 13, 2020·Frontiers in Pharmacology·Arun Suria Karnan MahendranCheng Foh Le
Oct 27, 2020·Bioscience Trends·Xueqin DongCuirong Zhao
Nov 20, 2020·Journal of Drug Targeting·Ghazaleh Jamalipour Soufi, Siavash Iravani
Nov 29, 2020·Signal Transduction and Targeted Therapy·Zezhong LiuShibo Jiang

❮ Previous
Next ❯

Methods Mentioned

BETA
circular dichroism
transgenic
enzyme-linked immunosorbent assay
ELISA
Assay
flow cytometry

Software Mentioned

GraphPad Prism
FlowJo
PyMOL Molecular Graphics System
PHASER
Schrödinger Suite
MolProbity
HKL3000
PyMOL
PHENIX
Swiss Model

Related Concepts

Trending Feeds

COVID-19

Coronaviruses encompass a large family of viruses that cause the common cold as well as more serious diseases, such as the ongoing outbreak of coronavirus disease 2019 (COVID-19; formally known as 2019-nCoV). Coronaviruses can spread from animals to humans; symptoms include fever, cough, shortness of breath, and breathing difficulties; in more severe cases, infection can lead to death. This feed covers recent research on COVID-19.

Blastomycosis

Blastomycosis fungal infections spread through inhaling Blastomyces dermatitidis spores. Discover the latest research on blastomycosis fungal infections here.

Nuclear Pore Complex in ALS/FTD

Alterations in nucleocytoplasmic transport, controlled by the nuclear pore complex, may be involved in the pathomechanism underlying multiple neurodegenerative diseases including Amyotrophic Lateral Sclerosis and Frontotemporal Dementia. Here is the latest research on the nuclear pore complex in ALS and FTD.

Applications of Molecular Barcoding

The concept of molecular barcoding is that each original DNA or RNA molecule is attached to a unique sequence barcode. Sequence reads having different barcodes represent different original molecules, while sequence reads having the same barcode are results of PCR duplication from one original molecule. Discover the latest research on molecular barcoding here.

Chronic Fatigue Syndrome

Chronic fatigue syndrome is a disease characterized by unexplained disabling fatigue; the pathology of which is incompletely understood. Discover the latest research on chronic fatigue syndrome here.

Evolution of Pluripotency

Pluripotency refers to the ability of a cell to develop into three primary germ cell layers of the embryo. This feed focuses on the mechanisms that underlie the evolution of pluripotency. Here is the latest research.

Position Effect Variegation

Position Effect Variagation occurs when a gene is inactivated due to its positioning near heterochromatic regions within a chromosome. Discover the latest research on Position Effect Variagation here.

STING Receptor Agonists

Stimulator of IFN genes (STING) are a group of transmembrane proteins that are involved in the induction of type I interferon that is important in the innate immune response. The stimulation of STING has been an active area of research in the treatment of cancer and infectious diseases. Here is the latest research on STING receptor agonists.

Microbicide

Microbicides are products that can be applied to vaginal or rectal mucosal surfaces with the goal of preventing, or at least significantly reducing, the transmission of sexually transmitted infections. Here is the latest research on microbicides.