scholarly journals 25-Hydroxycholesterol-Conjugated EK1 Peptide with Potent and Broad-Spectrum Inhibitory Activity against SARS-CoV-2, Its Variants of Concern, and Other Human Coronaviruses

2021 ◽  
Vol 22 (21) ◽  
pp. 11869
Author(s):  
Qiaoshuai Lan ◽  
Chao Wang ◽  
Jie Zhou ◽  
Lijue Wang ◽  
Fanke Jiao ◽  
...  
Keyword(s):  
Public Health ◽  
Antiviral Activity ◽  
Broad Spectrum ◽  
Fusion Inhibitor ◽  
Global Public Health ◽  
Newborn Mice ◽  
Viral Inhibitor ◽  
Modified Peptides ◽  
Human Coronaviruses ◽  
Enzymatic Product

The COVID-19 pandemic caused by SARS-CoV-2 infection poses a serious threat to global public health and the economy. The enzymatic product of cholesterol 25-hydroxylase (CH25H), 25-Hydroxycholesterol (25-HC), was reported to have potent anti-SARS-CoV-2 activity. Here, we found that the combination of 25-HC with EK1 peptide, a pan-coronavirus (CoV) fusion inhibitor, showed a synergistic antiviral activity. We then used the method of 25-HC modification to design and synthesize a series of 25-HC-modified peptides and found that a 25-HC-modified EK1 peptide (EK1P4HC) was highly effective against infections caused by SARS-CoV-2, its variants of concern (VOCs), and other human CoVs, such as HCoV-OC43 and HCoV-229E. EK1P4HC could protect newborn mice from lethal HCoV-OC43 infection, suggesting that conjugation of 25-HC with a peptide-based viral inhibitor was a feasible and universal strategy to improve its antiviral activity.

Brilacidin, a COVID-19 Drug Candidate, demonstrates broad-spectrum antiviral activity against human coronaviruses OC43, 229E and NL63 through targeting both the virus and the host cell

2021 ◽  
Author(s):  
Yanmei Hu ◽  
Hyunil Jo ◽  
William DeGrado ◽  
Jun Wang
Keyword(s):  
Antiviral Activity ◽  
Cell Surface ◽  
Host Cell ◽  
Mechanism Of Action ◽  
Broad Spectrum ◽  
Drug Candidate ◽  
Host Defense Peptides ◽  
Antibiotic Drug ◽  
Host Cell Surface ◽  
Human Coronaviruses

Brilacidin, a mimetic of host defense peptides (HDPs), is currently in phase 2 clinical trial as an antibiotic drug candidate. A recent study reported that brilacidin has antiviral activity against SARS-CoV-2 by inactivating the virus. In this work, we discovered an additional mechanism of action of brilacidin by targeting heparan sulfate proteoglycans (HSPGs) on host cell surface. Brilacidin, but not acetyl brilacidin, inhibits the entry of SARS-CoV-2 pseudovirus into multiple cell lines, and heparin, a HSPG mimetic, abolishes the inhibitory activity of brilacidin on SARS-CoV-2 pseudovirus cell entry. In addition, we found that brilacidin has broad-spectrum antiviral activity against multiple human coronaviruses (HCoVs) including HCoV-229E, HCoV-OC43, and HCoV-NL63. Mechanistic studies revealed that brilacidin has a dual antiviral mechanism of action including virucidal activity and binding to coronavirus attachment factor HSPGs on host cell surface. Brilacidin partially loses its antiviral activity when heparin was included in the cell cultures, supporting the host-targeting mechanism. Drug combination therapy showed that brilacidin has a strong synergistic effect with remdesivir against HCoV-OC43 in cell culture. Taken together, this study provides appealing findings for the translational potential of brilacidin as a broad-spectrum antiviral for coronaviruses including SARS-CoV-2.

scholarly journals A bivalent protein targeting glycans and HR1 domain in spike protein potently inhibited infection of SARS-CoV-2 and other human coronaviruses

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Yanxing Cai ◽  
Wei Xu ◽  
Jiayi Tang ◽  
Najing Cao ◽  
Qiaoshuai Lan ◽  
...  
Keyword(s):  
Cell Fusion ◽  
Mechanism Of Action ◽  
Broad Spectrum ◽  
Inhibitory Activity ◽  
Inhibitory Peptide ◽  
Newborn Mice ◽  
S Protein ◽  
Human Coronaviruses ◽  
Potent Inhibitory Activity ◽  
Cell Cell

Abstract Background Our previous studies have shown that combining the antiviral lectin GRFT and the pan-CoV fusion inhibitory peptide EK1 results in highly potent inhibitory activity against SARS-CoV-2 infection. In this study, we aimed to design and construct a bivalent protein consisting of GRFT and EK1 components and evaluate its inhibitory activity and mechanism of action against infection by SARS-CoV-2 and its mutants, as well as other human coronaviruses (HCoVs). Methods The bivalent proteins were expressed in E. coli and purified with Ni-NTA column. HIV backbone-based pseudovirus (PsV) infection and HCoV S-mediated cell–cell fusion assays were performed to test their inhibitory activity. ELISA and Native-PAGE were conducted to illustrate the mechanism of action of these bivalent proteins. Five-day-old newborn mice were intranasally administrated with a selected bivalent protein before or after HCoV-OC43 challenge, and its protective effect was monitored for 14 days. Results Among the three bivalent proteins purified, GL25E exhibited the most potent inhibitory activity against infection of SARS-CoV-2 PsVs expressing wild-type and mutated S protein. GL25E was significantly more effective than GRFT and EK1 alone in inhibiting HCoV S-mediated cell–cell fusion, as well as infection by SARS-CoV-2 and other HCoVs, including SARS-CoV, MERS-CoV, HCoV-229E, HCoV-NL63 and HCoV-OC43. GL25E could inhibit authentic SASR-CoV-2, HCoV-OC43 and HCoV-229E infection in vitro and prevent newborn mice from authentic HCoV-OC43 infection in vivo. GL25E could bind to glycans in the S1 subunit and HR1 in the S2 subunit in S protein, showing a mechanism of action similar to that of GRFT and EK1 alone. Conclusions Since GL25E showed highly potent and broad-spectrum inhibitory activity against infection of SARS-CoV-2 and its mutants, as well as other HCoVs, it is a promising candidate for further development as a broad-spectrum anti-HCoV therapeutic and prophylactic to treat and prevent COVID-19 and other emerging HCoV diseases.

scholarly journals Inhibition of SARS-CoV-2 infection (previously 2019-nCoV) by a highly potent pan-coronavirus fusion inhibitor targeting its spike protein that harbors a high capacity to mediate membrane fusion

2020 ◽  
Author(s):  
Shuai Xia ◽  
Meiqin Liu ◽  
Chao Wang ◽  
Wei Xu ◽  
Qiaoshuai Lan ◽  
...  
Keyword(s):  
Membrane Fusion ◽  
High Capacity ◽  
Fusion Inhibitor ◽  
Amino Acid Residues ◽  
Global Public Health ◽  
S Protein ◽  
Helical Bundle ◽  
Recent Outbreak ◽  
Human Coronaviruses ◽  
Treatment Of Infection

AbstractThe recent outbreak of coronavirus disease (COVID-19) caused by SARS-CoV-2 infection in Wuhan, China has posed a serious threat to global public health. To develop specific anti-coronavirus therapeutics and prophylactics, the molecular mechanism that underlies viral infection must first be confirmed. Therefore, we herein used a SARS-CoV-2 spike (S) protein-mediated cell-cell fusion assay and found that SARS-CoV-2 showed plasma membrane fusion capacity superior to that of SARS-CoV. We solved the X-ray crystal structure of six-helical bundle (6-HB) core of the HR1 and HR2 domains in SARS-CoV-2 S protein S2 subunit, revealing that several mutated amino acid residues in the HR1 domain may be associated with enhanced interactions with HR2 domain. We previously developed a pan-coronavirus fusion inhibitor, EK1, which targeted HR1 domain and could inhibit infection by divergent human coronaviruses tested, including SARS-CoV and MERS-CoV. We then generated a series of lipopeptides and found that the EK1C4 was the most potent fusion inhibitor against SARS-CoV-2 S protein-mediated membrane fusion and pseudovirus infection with IC50s of 1.3 and 15.8 nM, about 241- and 149-fold more potent than that of EK1 peptide, respectively. EK1C4 was also highly effective against membrane fusion and infection of other human coronavirus pseudoviruses tested, including SARS-CoV and MERS-CoV, as well as SARSr-CoVs, potently inhibiting replication of 4 live human coronaviruses, including SARS-CoV-2. Intranasal application of EK1C4 before or after challenge with HCoV-OC43 protected mice from infection, suggesting that EK1C4 could be used for prevention and treatment of infection by currently circulating SARS-CoV-2 and emerging SARSr-CoVs.

scholarly journals Broad-spectrum in vitro antiviral activity of ODBG-P-RVn: an orally-available, lipid-modified monophosphate prodrug of remdesivir parent nucleoside (GS-441524)

2021 ◽  
Author(s):  
Michael K Lo ◽  
Punya Shrivastava-Ranjan ◽  
Payel Chatterjee ◽  
Mike Flint ◽  
James R Beadle ◽  
...  
Keyword(s):  
Public Health ◽  
Antiviral Activity ◽  
Broad Spectrum ◽  
Airway Epithelial Cells ◽  
Health Concern ◽  
Airway Epithelial ◽  
Public Health Concern ◽  
Small Airway Epithelial Cells

The intravenous administration of remdesivir for COVID-19 confines its utility to hospitalized patients. We evaluated the broad-spectrum antiviral activity of ODBG-P-RVn, an orally available, lipid-modified monophosphate prodrug of the remdesivir parent nucleoside (GS-441524) against viruses that cause diseases of human public health concern, including SARS-CoV-2. ODBG-P-RVn showed 20-fold greater antiviral activity than GS-441524 and had near-equivalent activity to remdesivir in primary-like human small airway epithelial cells. Our results warrant investigation of ODBG-P-RVn efficacy in vivo.

scholarly journals Profiling COVID-19 Genetic Research: A Data-Driven Study Utilizing Intelligent Bibliometrics

2021 ◽  
Vol 6 ◽  
Author(s):  
Mengjia Wu ◽  
Yi Zhang ◽  
Mark Grosser ◽  
Steven Tipper ◽  
Deon Venter ◽  
...  
Keyword(s):  
Public Health ◽  
Gene Expression ◽  
Vaccine Development ◽  
Genetic Research ◽  
The United States ◽  
Human Society ◽  
Global Public Health ◽  
Health Administration ◽  
Disease Spectrum ◽  
Human Coronaviruses

The COVID-19 pandemic constitutes an ongoing worldwide threat to human society and has caused massive impacts on global public health, the economy and the political landscape. The key to gaining control of the disease lies in understanding the genetics of SARS-CoV-2 and the disease spectrum that follows infection. This study leverages traditional and intelligent bibliometric methods to conduct a multi-dimensional analysis on 5,632 COVID-19 genetic research papers, revealing that 1) the key players include research institutions from the United States, China, Britain and Canada; 2) research topics predominantly focus on virus infection mechanisms, virus testing, gene expression related to the immune reactions and patient clinical manifestation; 3) studies originated from the comparison of SARS-CoV-2 to previous human coronaviruses, following which research directions diverge into the analysis of virus molecular structure and genetics, the human immune response, vaccine development and gene expression related to immune responses; and 4) genes that are frequently highlighted include ACE2, IL6, TMPRSS2, and TNF. Emerging genes to the COVID-19 consist of FURIN, CXCL10, OAS1, OAS2, OAS3, and ISG15. This study demonstrates that our suite of novel bibliometric tools could help biomedical researchers follow this rapidly growing field and provide substantial evidence for policymakers’ decision-making on science policy and public health administration.

scholarly journals Antivirals against human and animal Coronaviruses: different approach in SARS-CoV-2 treatment

2020 ◽  
Author(s):  
Igor Andrade Santos ◽  
Victória Riquena Grosche ◽  
Robinson Sabino-Silva ◽  
Ana Carolina Gomes Jardim
Keyword(s):  
Public Health ◽  
Antiviral Activity ◽  
Biological Activities ◽  
Severe Disease ◽  
Novel Therapies ◽  
Global Public Health ◽  
Novel Approaches

Coronaviruses (CoVs) is a group of viruses from Coronaviridae family which are able to infect human and animals, causing mild to severe disease. The recently emergence of SARS-CoV-2, worldwide classified as a pandemic disease represent a threat to global public health. Associated with the high transmissibility, the lack of vaccine and antivirals drugs demonstrates the need to develop novel therapies to treat infected patients. This review aims to summarize compounds from 2005 up to now with already described antiviral activity in vitro and in vivo to human and animal CoVs. These compounds may present as a source of molecules with potent biological activities which could be further investigated for their use as novel approaches against SARS-CoV-2.

Life Lessons of the Pandemic ”Covid - 19”

2020 ◽  
Vol 11 (SPL1) ◽  
pp. 469-471 ◽  
Author(s):  
Bhagyashri Vijay Chaudhari ◽  
Priya P. Chawle
Keyword(s):  
Public Health ◽  
Review Article ◽  
Public Health Emergency ◽  
The Novel ◽  
Global Public Health ◽  
Strange Situation ◽  
Republic Of China ◽  
Lifetime History ◽  
The People ◽  
Life Lessons

“A lesson learned the hard way is a lesson learned for a lifetime.” Every bad situation hurts; however, it sure does teach us something a lesson. In the same manner of a new lesson for Human lifetime, history is observing 'The Novel COVID-19 ’, a very horrible and strange situation created due to fighting with a microscopic enemy. WHO on 11 February 2020 has announced a name for new disease as - 19 and has declared as a global public health emergency and subsequently as pandemic because of its widespread. This began as an outbreak in December 2019, with its in Wuhan, the People Republic of China has emerged as a public health emergency of international concern. is the group of a virus with non-segmented, single-stranded and positive RNA genome. This bad situation of pandemic creates new scenes in the life of people in a different manner, which will be going to be life lessons for them. Such lessons should be kept in mind for the safety of living beings and many more things. In this narrative review article, reference was taken from a different article published in various databases which include the view of different authors and writers on the "Lessons to be from Corona".

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