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SARS-CoV-2 entry inhibitor exhibits antiviral activity




New research published in Virology Journal Uses a combination of computer-aided drug design (CADD) approach and cell-based In vitro Assay to identify 5 potential severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) inhibitors. Two of the five inhibitors showed antiviral activity against SARS-CoV-2 and new mutants from South Africa and Scotland.

study: Discovery and evaluation of entry inhibitors for SARS-CoV-2 and its new mutants.. Image Credit: Kateryna Kon / Shutterstock

Need to develop powerful antivirals

Due to the urgency of the pandemic and the severity of the disease, attempts have been made to reuse several treatment candidates to treat coronavirus disease 2019 (COVID-19). In the United States, only remdesivir is approved for the treatment of hospitalized COVID-19 patients. However, according to a clinical study by the World Health Organization (WHO), remdesivir showed no significant effect on hospitalized COVID-19 patients.

Many people are hesitant to take the new vaccine developed against SARS-CoV-2. Vaccine availability is also an issue in some places. For these reasons, 100% vaccination may not be possible. On the other hand, children, pregnant women and individuals with weakened immunity remain vulnerable.

Also, due to the emergence of new mutant strains (VOCs) of concern Effectiveness of The vaccine is at risk. Therefore, it is necessary to develop antiviral drugs for the treatment of COVID-19.

Principles for developing powerful antivirals

SAR-CoV-2 binds to host cells via the receptor binding domain (RBD) of peplomer (S) proteins, especially S proteins. RBD binds to the host cell’s receptor, angiotensin converting enzyme 2 (ACE2). This binding is a major determinant of cell invasion and is an excellent target for the development of antiviral agents.

S-RBD / ACE2 binding is well-studied as it is one of the key events early in the life cycle of the SARS-CoV-2 virus. There are two studies on the high resolution crystal structures of RBD and ACE2. Careful examination of these structures reveals a properly sized pocket for designing the drag using. In silico approach.

In silico Approach to develop powerful antiviral agents

Researchers have used a CADD approach to test approximately 8 million drug-like compounds that can be physically and chemically docked in S-RBD / ACE2 pockets. These small molecules can block S-RBD / ACE2 interactions. The top 500 compounds were redocked and the results were manually visualized for the interactions between the compounds and S-RBD / ACE2.

Calculated pharmacological properties and ADMET (absorption, distribution, metabolism, excretion, and toxicity) determine the safety, uptake, elimination, metabolic behavior, and efficacy of a compound. According to these, 5 compounds were selected. They were all drug discoverable. These were further investigated for SARS-CoV-2 inhibitory activity. In vitro Assay.

In vitro Assay for evaluating potent antiviral agents

Evaluating that it blocks the S-RBD / ACE2 bond, all five compounds can block this bond to varying degrees.

Next, researchers used a lentivirus to screen for possible inhibition of compound invasion. Pseudovirus Representing SARS-CoV-2 Spike protein This is because it mimics the SARS-CoV-2 entry in the host cell. Two compounds, MU-UNMC-1 and MU-UNMC-2, may block the entry of the virus into the host cell.

These two compounds were further tested for their antiviral effect on SARS-CoV-2 isolates. In these SARS-CoV-2 infection assays, both compounds showed antiviral activity in human bronchial epithelial cells. They were also able to effectively block the replication of South African and Scottish variants. The two VOCs propagate rapidly.

Antiviral efficacy was tested after various addition times to SARS-CoV-2 infected cells to determine at what stage of the viral life cycle the compound exhibited antiviral efficacy.

Addition of the compound 2 hours after infection was observed to reduce SARS-CoV-2 infectivity by 80%. A 40% reduction in SARS-CoV-2 infectivity was observed when added at the time of infection. No reduction was observed when added 4 hours after infection.

Therefore, the two compounds tested were entry inhibitors that blocked the virus from entering the host cell by interacting with the S-RBD / ACE2 binding interface.

In addition, the researchers evaluated the antiviral effect of the compound in combination with remdesivir. The combination of remdesivir and MU-UNMC-1 showed an antagonistic effect, and remdesivir and MU-UNMC-2 showed a synergistic effect.


Researchers used the SwissADME Web Portal to calculate the biophysical properties of MU-UNMC-2, a compound that demonstrated antiviral and synergistic effects with remdesivir.

According to this, the compound is predicted to be highly permeable, moderately soluble and less toxic. Pharmacokinetic data show that the compound has high gastrointestinal absorption. MU-UNMC-2 was also predicted to show high drug potential.

Further research

In this study, two SARS-CoV-2 entry inhibitors were identified and tested. These compounds fall into the drug-like category. MU-UNMC-2, alone or in combination with remdesivir, showed antiviral activity against the original virus isolate against two new mutant variants. MU-UNMC-2 has a good physicochemical profile and can be considered in preclinical studies. After verification, it may be a prophylactic or therapeutic agent for COVID-19.

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