How the coronavirus could be prevented from invading a host cell

UC Riverside-led study shows inhibiting two host cell proteases could help prevent COVID-19

Newswise — RIVERSIDE, Calif. -- How might the novel coronavirus be prevented from entering a host cell in an effort to thwart infection? A team of biomedical scientists has made a discovery that points to a solution.

The scientists, led by Maurizio Pellecchia in the School of Medicine at the University of California, Riverside, report in the journal Molecules that two proteases -- enzymes that break down proteins -- located on the surface of host cells and responsible for processing viral entry could be inhibited. Such protease inhibition would prevent SARS-CoV2, the coronavirus responsible for COVID-19, from invading the host cell.

The research is featured as the cover story of the journal (Volume 25, Issue 10).

Spike glycoprotein

The outer surface of coronaviruses contains a critical protein called spike glycoprotein, or S-glycoprotein. Responsible for giving the coronavirus its typical crown shape, the S-glycoprotein is essential for the entry of viral particles into host cells. Host cell proteases, however, must first process or cut this viral surface protein to allow the virus to enter the cells.

Pellecchia's lab and others have recognized that in addition to a previously identified protease called TMPRSS2, the new SARS-CoV2 coronavirus could also be processed by an additional human protease, called furin, for viral entry.

"The use of the host protease furin for processing is a common mechanism of cell entry by both viral fusion proteins and certain bacterial toxins," said Pellecchia, a professor of biomedical sciences, who led the research team. "SARS-CoV2 uses this mechanism also. The nature of the 'proteolytic cleavage' in its S-glycoprotein can determine whether this virus can be transmitted across species, for example from bats or camels to humans."

A fusion protein combines the attributes of more than one protein. Proteolytic cleavage refers to the process of breaking the peptide bonds between amino acids in a protein, which results in cutting the protein.

The coronavirus S-glycoprotein contains three cleavage sites that human host proteases process. The exact nature and sequence of these cleavage sites, and their respective processing proteases, can determine the level of pathogenicity and whether the virus can cross species.

Spotlight on inhibitors

Pellecchia explained that the anthrax toxin, similar to SARS-CoV2, requires processing by human furin to infect macrophages, a type of white blood cell. Using anthrax toxin as model system, his team found an inhibitor of both TMPRSS2 and furin in cellular and animal models can efficiently suppress cell entry by the toxin.

clinical trial with COVID-19 patients recently began using the TMPRSS2 inhibitor camostat.

"We found, however, that camostat is a poor furin inhibitor," Pellecchia said. "Our current study, therefore, calls for the development of additional protease inhibitors or inhibitor-cocktails that can simultaneously target both TMPRSS2 and furin and suppress SARS-CoV2 from entering the host cell."

Pellecchia added that until now the presence of a furin cleavage site in SARS-CoV2 had been linked to increased pathogenicity. But genetic elimination of furin in cellular laboratory studies failed to stop viral entry, suggesting TMPRSS2 remains the most relevant protease.

Using peptide sequences from SARS-CoV2 S-glycoprotein, however, his team has now demonstrated the new mutations in this coronavirus strain resulted in efficient and increased processing of viral entry by furin and TMPRSS2.

"In other words, SARS-CoV2, unlike other less pathogenic strains, can more efficiently use both proteases, TMPRSS2 and furin, to start the invasion of host cells," Pellecchia said. "While TMPRSS2 is more abundant in the lungs, furin is expressed in other organs, perhaps explaining why SARS-CoV2 is capable of invading and damaging multiple organs."

Pellecchia's lab has already identified potent and effective preclinical inhibitors of furin and demonstrated these inhibitors could be developed as potential COVID-19 therapeutics, perhaps in combination with drugs such as camostat, the TMPRSS2 inhibitor.

Funding sought

"We are seeking additional funding to pursue the design and development of dual inhibitors that can simultaneously target both TMPRSS2 and furin," Pellecchia said. "The funding would allow us to explore new possible effective therapeutics against COVID-19 and support studies that could have far reaching applications to ward off possible future pandemics resulting from similar activating mutations in other viral strains."

Pellecchia, who holds the Daniel Hays Chair in Cancer Research at the UCR School of Medicine, was joined in the research by Elisa Barile, Carlo Baggio, and Luca Gambini of UCR; and Sergey A. Shiryaev and Alex Y. Strongin of the Sanford Burnham Prebys Medical Discovery Institute in La Jolla.

###

The study was supported by grants to Pellecchia from the National Institutes of Health.

The research paper is titled, "Potential Therapeutic Targeting of Coronavirus Spike Glycoprotein Priming."

The University of California, Riverside (http://www.ucr.edu) is a doctoral research university, a living laboratory for groundbreaking exploration of issues critical to Inland Southern California, the state and communities around the world. Reflecting California's diverse culture, UCR's enrollment is more than 24,000 students. The campus opened a medical school in 2013 and has reached the heart of the Coachella Valley by way of the UCR Palm Desert Center. The campus has an annual statewide economic impact of almost $2 billion. To learn more, email news@ucr.edu.

SEE ORIGINAL STUDY




Filters close

Showing results

110 of 4219
Released: 4-Dec-2020 4:30 PM EST
New review confirms disproportionate impact of COVID-19 on Black, Hispanic populations
Oregon Health & Science University

Black and Hispanic populations are disproportionately affected by COVID-19, according to a systematic review published this week.

Newswise: 250647_web.jpg
Released: 4-Dec-2020 4:05 PM EST
For nationalistic regimes, similar COVID-19 policies are the sincerest form of flattery
University of Texas at Arlington

Analysis from a University of Texas at Arlington assistant professor of public policy suggests that nationalistic governments around the globe are more likely to copy other nationalistic governments in responding to the current pandemic.

Released: 4-Dec-2020 3:15 PM EST
New Study Finds Once Hospitalized, Black Patients with COVID-19 Have Lower Risk of Death than White Patients
NYU Langone Health

A team of investigators at NYU Langone Health has found that once hospitalized, Black patients (after controlling for other serious health conditions and neighborhood income) were less likely to have severe illness, die, or be discharged to hospice compared to White patients.

Released: 4-Dec-2020 2:35 PM EST
AANA Commends CDC on Prioritizing COVID-19 Vaccine Distribution to Healthcare Personnel
American Association of Nurse Anesthetists (AANA)

The American Association of Nurse Anesthetists (AANA) commends the U.S. Centers for Disease Control and Prevention’s (CDC's) team of advisors on prioritizing frontline healthcare personnel and residents of long-term facilities for the first phase of the COVID-19 vaccine distribution.

Released: 4-Dec-2020 1:50 PM EST
COVID-19 in Victorian schools and childcare mainly driven by community transmission
Murdoch Childrens Research Institute

Analysis of Victorian data by the Murdoch Children's Research Institute suggests that COVID-19 cases in schools and childcare were mainly driven by community transmission

Released: 4-Dec-2020 12:20 PM EST
Identifying markers of COVID-19 infection using blood tests
University of Seville

Researchers from the Institute of Biomedicine of Seville (IBIS) have presented a study carried out in the Clinical Biochemistry Service of the Virgen del Rocío University Hospital which identifies the values for six biochemical biomarkers that indicate a patient may be infected with SARS-COV-2 (COVID-19).

Released: 4-Dec-2020 12:05 PM EST
Research confirms crucial monitoring assessment is effective for patients with COVID-19
University of Portsmouth

A combined research team from the Universities of Portsmouth and Bournemouth and Portsmouth Hospitals University NHS Trust has shown that an assessment score used to measure a patient's severity of illness can be applied to patients with Covid-19 without modification.

Newswise:Video Embedded flccc-alliance-calls-on-national-health-authorities-to-immediately-review-medical-evidence-showing-the-efficacy-of-ivermectin-for-the-prevention-of-covid-19-and-as-an-early-outpatient-treatment
VIDEO
Released: 4-Dec-2020 12:00 PM EST
FLCCC Alliance Calls on National Health Authorities to Immediately Review Medical Evidence Showing the Efficacy of Ivermectin for the Prevention of COVID-19 and as an Early Outpatient Treatment
Front Line COVID-19 Critical Care Alliance (FLCCC Alliance)

“Following the swi. review— and subsequent guidance— by the NIH and theCDC of Ivermectin, we expect that Ivermectin’s widespread, immediate use willallow for a rapid and safe re-opening of businesses and schools across the nation—and quickly reduce the strain on overwhelmed ICUs.” —FLCCC Alliance

Released: 4-Dec-2020 11:50 AM EST
Immunity passports: Ethical conflict and opportunity
University of the Basque Country

Immunity passports are a means of registering whether an individual has developed immunity to COVID-19 and is therefore unlikely to either catch or spread the disease.


Showing results

110 of 4219

close
2.00019