Existing FDA-Approved Drugs Could Help Fight COVID-19 Disease | Medicine | Sci-News.com

 sci-news.com  03/26/2020 21:17:25 

Drugs that are already approved by the U.S. Food and Drug Administration (FDA) could hold promise in fighting COVID-19, a respiratory disease caused by the SARS-CoV-2 coronavirus, according to a new modeling study from the University of Texas Southwestern Medical Center.

This scanning electron microscope image shows SARS-CoV-2 (round gold objects) emerging from the surface of cells cultured in the lab. The virus shown was isolated from a patient in the U.S. Image credit: NIAID-RML.

This scanning electron microscope image shows SARS-CoV-2 (round gold objects) emerging from the surface of cells cultured in the lab. The virus shown was isolated from a patient in the U.S. Image credit: NIAID-RML.

Developing new pharmaceutical agents that work against this virus could take months, even with rapid approval, said Professor Hesham Sadek, senior author of the study.

Thats why we looked to drugs that are already FDA approved, a strategy thats become increasingly popular in disease research.

Most drugs exert their effects by binding to specific targets in the body or on disease-causing bacteria or viruses, attaching to proteins, receptors, or channels to alter their function.

However, almost all drugs cause side effects due to off-target effects, attaching to areas that are unintended.

Professor Sadek and colleagues reasoned that some FDA-approved drugs might unintentionally target vulnerable parts of SARS-CoV-2.

To test this idea, they performed a computer-based study to broadly examine which drugs might be useful against this coronavirus.

They focused on SARS-CoV-2s main protease (SARS-CoV-2 Mpro), an enzyme that the virus uses to bind long strands of proteins that it directs host cells to generate for the virus own replication and cut them into smaller pieces.

3D structure of SARS-CoV-2 Mpro, in two different views. One protomer of the dimer is shown in light blue, the other one in orange. Domains are labeled by Roman numbers. Amino-acid residues of the catalytic site are indicated as yellow and blue spheres, for Cys145 and His41, respectively. An asterisk marks a residue from protomer B (orange). Black spheres indicate the positions of Ala285 of each of the two domains III. Chain termini are labeled N and C for molecule A (light blue) and N* and C* for molecule B (orange). Image credit: Zhang et al, doi: 10.1126/science.abb3405.

3D structure of SARS-CoV-2 Mpro, in two different views. One protomer of the dimer is shown in light blue, the other one in orange. Domains are labeled by Roman numbers. Amino-acid residues of the catalytic site are indicated as yellow and blue spheres, for Cys145 and His41, respectively. An asterisk marks a residue from protomer B (orange). Black spheres indicate the positions of Ala285 of each of the two domains III. Chain termini are labeled N and C for molecule A (light blue) and N* and C* for molecule B (orange). Image credit: Zhang et al, doi: 10.1126/science.abb3405.

Scientists elsewhere recently elucidated the structure of this enzyme, including its binding pocket, Professor Sadek said.

A drug that strongly attaches to this binding pocket could block its function, rendering the virus unable to multiply and propagate infection.

To identify drug candidates, the researchers used a computer program that structurally matched all FDA drugs to the binding pocket.

They then manually examined which drugs that fit structurally might forge strong chemical bonds with the pocket once inside.

Two-dimensional presentation of docking poses for top 11 candidate drugs. Blue arrows are backbone hydrogen bonds and green arrows are the side chain hydrogen bonds. Image credit: Farag et al, doi: 10.26434/chemrxiv.12003930.v1.

Two-dimensional presentation of docking poses for top 11 candidate drugs. Blue arrows are backbone hydrogen bonds and green arrows are the side chain hydrogen bonds. Image credit: Farag et al, doi: 10.26434/chemrxiv.12003930.v1.

Unsurprisingly, their top hits included several antiviral drugs, including Darunavir, Nelfinavir, and Saquinavir, which work by targeting proteases.

However, the scientists also identified several candidates that fall far outside antiviral use. These included the ACE inhibitor Moexipril; chemotherapeutic agents Daunorubicin and Mitoxantrone; Metamizole, a painkiller; the antihistamine Bepotastine; and the anti-malarial drug Atovaquone.

One of the most promising candidates was Rosuvastatin, a statin thats sold under the brand name Crestor and is already taken by millions of patients around the world to lower their cholesterol.

Although several candidates are probably unsuitable to give to critically ill patients — such as the chemotherapeutic agents — Rosuvastatin already exhibits a strong safety profile, is inexpensive, and is readily available, Professor Sadek said.

Because this study was completely computer-based, its unknown if any of these candidates will actually be active against SARS-CoV-2, and additional validation studies are needed before any clinical application.

But the study gives a starting point for other researchers to evaluate these drugs both in the lab and in patients.

Repurposing these FDA-approved drugs could be a fast way to get treatment to patients who otherwise have no option.

The study is published on the ChemRxiv.org preprint server.

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Ayman Farag et al. 2020. Identification of FDA Approved Drugs Targeting COVID-19 Virus by Structure-Based Drug Repositioning. ChemRxiv, doi: 10.26434/chemrxiv.12003930.v1

This article is based on text provided by the University of Texas Southwestern Medical Center.

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