Three configurations of active sites where inhibitor GC-376 binds with the COVID-19 virus’s main protease (drug target Mpro), as depicted by 3D computer modeling. Credit: Image generated by Yu Chen, University of South Florida Health, using X-ray crystallography
Four promising antiviral drug candidates identified and analyzed by a University of Arizona-University of South Florida team in the preclinical study.
As the death toll from the COVID-19 pandemic mounts, scientists worldwide continue their push to develop effective treatments and a vaccine for the highly contagious respiratory virus.
University of South Florida Health (USF Health) Morsani College of Medicine scientists recently worked with colleagues at the University of Arizona College of Pharmacy to identify several existing compounds that block replication of the COVID-19 virus (SARS-CoV-2) within human cells grown in the laboratory. The inhibitors all demonstrated potent chemical and structural interactions with a viral protein critical to the virus’s ability to proliferate.
The research team’s drug discovery study was published on June 15, 2020, in Cell Research, a high-impact Nature journal.
The most promising drug candidates – including the FDA-approved hepatitis C medication boceprevir and an investigational veterinary antiviral drug known as GC-376 – target the SARS-CoV-2 main protease (Mpro), an enzyme that cuts out proteins from a long strand that the virus produces when it invades a human cell. Without Mpro, the virus cannot replicate and infect new cells. This enzyme had already been validated as an antiviral drug target for the original SARS and MERS, both genetically similar to SARS-CoV-2.
“With a rapidly emerging infectious disease like COVID-19, we don’t have time to develop new antiviral drugs from scratch,” said Yu Chen, PhD, USF Health associate professor of molecular medicine and a coauthor of the Cell Research paper. “A lot of good drug candidates are already out there as a starting point. But, with new information from studies like ours and current technology, we can help design even better (repurposed) drugs much faster.”
Before the pandemic, Dr. Chen applied his expertise in structure-based drug design to help develop inhibitors (drug compounds) that target bacterial enzymes causing resistance to certain commonly prescribed antibiotics such as penicillin. Now his laboratory focuses its advanced techniques, including X-ray crystallography and molecular docking, on looking for ways to stop SARS-CoV-2.
Mpro represents an attractive target for drug development against COVID-19 because of the enzyme’s essential role in the life cycle of the coronavirus and the absence of a similar protease in humans, Dr. Chen said. Since people do not have the enzyme, drugs targeting this protein are less likely to cause side effects, he explained.
The four leading drug candidates identified by the University of Arizona-USF Health team as the best (most potent and specific) for fighting COVID-19 are described below. These inhibitors rose to the top after screening more than 50 existing protease compounds for potential repurposing:
Boceprevir, a drug to treat Hepatitis C, is the only one of the four compounds already approved by the FDA. Its effective dose, safety profile, formulation and how the body processes the drug (pharmacokinetics) are already known, which would greatly speed up the steps needed to get boceprevir to clinical trials for COVID-19, Dr. Chen said.
GC-376, an investigational veterinary drug for a deadly strain of coronavirus in cats, which causes feline infectious peritonitis. This agent was the most potent inhibitor of the Mpro enzyme in biochemical tests, Dr. Chen said, but before human trials could begin it would need to be tested in animal models of SARS-CoV-2. Dr. Chen and his doctoral student Michael Sacco determined the X-ray crystal structure of GC-376 bound by Mpro, and characterized molecular interactions between the compound and viral enzyme using 3D computer modeling.
Calpain inhibitors II and XII, cysteine inhibitors investigated in the past for cancer, neurodegenerative diseases and other conditions, also showed strong antiviral activity. Their ability to dually inhibit both Mpro and calpain/cathepsin protease suggests these compounds may include the added benefit of suppressing drug resistance, the researchers report.
All four compounds were superior to other Mpro inhibitors previously identified as suitable to clinically evaluate for treating SARS-CoV-2, Dr. Chen said.
A promising drug candidate – one that kills or impairs the virus without destroying healthy cells — fits snugly, into the unique shape of viral protein receptor’s “binding pocket.” GC-376 worked particularly well at conforming to (complementing) the shape of targeted Mpro enzyme binding sites, Dr. Chen said. Using a lock (binding pocket, or receptor) and key (drug) analogy, “GC-376 was by far the key with the best, or tightest, fit,” he added. “Our modeling shows how the inhibitor can mimic the original peptide substrate when it binds to the active site on the surface of the SARS-CoV-2 main protease.”
Instead of promoting the activity of viral enzyme, like the substrate normally does, the inhibitor significantly decreases the activity of the enzyme that helps SARS-CoV-2 make copies of itself.
Visualizing 3-D interactions between the antiviral compounds and the viral protein provides a clearer understanding of how the Mpro complex works and, in the long-term, can lead to the design of new COVID-19 drugs, Dr. Chen said. In the meantime, he added, researchers focus on getting targeted antiviral treatments to the frontlines more quickly by tweaking existing coronavirus drug candidates to improve their stability and performance.
Reference: “Boceprevir, GC-376, and calpain inhibitors II, XII inhibit SARS-CoV-2 viral replication by targeting the viral main protease” by Chunlong Ma, Michael Dominic Sacco, Brett Hurst, Julia Alma Townsend, Yanmei Hu, Tommy Szeto, Xiujun Zhang, Bart Tarbet, Michael Thomas Marty, Yu Chen and Jun Wang, 15 June 2020, Cell Research. DOI: 10.1038/s41422-020-0356-z
NASA’s Voyager 1 spacecraft is depicted in this artist’s concept traveling through interstellar space, or the space between stars, which it entered in 2012. Credit: NASA/JPL-Caltech
For the first time since November, NASA’s Voyager 1 spacecraft is returning usable data about the health and status of its onboard engineering systems. The next step is to enable the spacecraft to begin returning science data again. The probe and its twin, Voyager 2, are the only spacecraft to ever fly in interstellar space (the space between stars).
Voyager 1 stopped sending readable science and engineering data back to Earth on Nov. 14, 2023, even though mission controllers could tell the spacecraft was still receiving their commands and otherwise operating normally. In March, the Voyager engineering team at NASA’s Jet Propulsion Laboratory in Southern California confirmed that the issue was tied to one of the spacecraft’s three onboard computers, called the flight data subsystem (FDS). The FDS is responsible for packaging the science and engineering data before it’s sent to Earth.
The team discovered that a single chip responsible for storing a portion of the FDS memory—including some of the FDS computer’s software code—isn’t working. The loss of that code rendered the science and engineering data unusable. Unable to repair the chip, the team decided to place the affected code elsewhere in the FDS memory. But no single location is large enough to hold the section of code in its entirety.
So they devised a plan to divide affected the code into sections and store those sections in different places in the FDS. To make this plan work, they also needed to adjust those code sections to ensure, for example, that they all still function as a whole. Any references to the location of that code in other parts of the FDS memory needed to be updated as well.
After receiving data about the health and status of Voyager 1 for the first time in five months, members of the Voyager flight team celebrate in a conference room at NASA’s Jet Propulsion Laboratory on April 20. Credit: NASA/JPL-Caltech
The team started by singling out the code responsible for packaging the spacecraft’s engineering data. They sent it to its new location in the FDS memory on April 18. A radio signal takes about 22.5 hours to reach Voyager 1, which is over 15 billion miles (24 billion kilometers) from Earth, and another 22.5 hours for a signal to come back to Earth. When the mission flight team heard back from the spacecraft on April 20, they saw that the modification had worked: For the first time in five months, they have been able to check the health and status of the spacecraft.
During the coming weeks, the team will relocate and adjust the other affected portions of the FDS software. These include the portions that will start returning science data.
Voyager 2 continues to operate normally. Launched over 46 years ago, the twin Voyager spacecraft are the longest-running and most distant spacecraft in history. Before the start of their interstellar exploration, both probes flew by Saturn and Jupiter, and Voyager 2 flew by Uranus and Neptune.
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Osoyoos commuters can celebrate Earth Day as the Town joins in on a national commuter challenge known as “Leg Day,” entering a chance to win sustainable transportation prizes.
The challenge, from Earth Day Canada, is to record 10 sustainable commutes taken without a car.
“Cars are one of the biggest contributors to gas emissions in Canada,” reads an Earth Day Canada statement. “That’s why, Earth Day Canada is launching the national Earth Day is Leg Day Challenge.”
So far, over 42.000 people have participated in the Leg Day challenge.
Participants could win an iGo electric bike, public transportation for a year, or a gym membership.
The Town of Osoyoos put out a message Monday promoting joining the national program.
For more information on the Leg Day challenge click here.
Verticillium wilt is a problem for a lot of crops in Manitoba, including canola, sunflowers and alfalfa.
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In potatoes, the fungus Verticillium dahlia is the main cause of potato early die complex. In a 2021 interview with the Co-operator, Mario Tenuta, University of Manitoba soil scientist and main investigator with the Canadian Potato Early Dying Network, suggested the condition can cause yield loss of five to 20 per cent. Other research from the U.S. puts that number as high as 50 per cent.
It also becomes a marketing issue when stunted spuds fall short of processor preferences.
Verticillium in potatoes can significantly reduce yield and, being soil-borne, is difficult to manage.
Preliminary research results suggest earlier planting of risk-prone fields could reduce losses, in part due to colder soil temperatures earlier in the season.
Unlike other potato fungal issues that can be addressed with foliar fungicide, verticillium hides in the soil.
“Commonly we use soil fumigation and that’s very expensive,” said Julie Pasche, plant pathologist with North Dakota State University.
There are options. In 2017, labels expanded for the fungicide Aprovia, Syngenta’s broad-spectrum answer for leaf spots or powdery mildews in various horticulture crops. In-furrow verticillium suppression for potatoes was added to the label.
There has also been interest in biofumigation. Mustard has been tagged as a potential companion crop for potatoes, thanks to its production of glucosinolate and the pathogen- and pest-inhibiting substance isothiocyanate.
Last fall, producers heard that a new, sterile mustard variety specifically designed for biofumigation had been cleared for sale in Canada, although seed supplies for 2024 are expected to be slim. AAC Guard was specifically noted for its effectiveness against verticillium wilt.
Timing is everything
Researchers at NDSU want to study the advantage of natural plant growth patterns.
“What we’d like to look at are other things we can do differently, like verticillium fertility management and water management, as well as some other areas and how they may be affected by planting date,” Pasche said.
The idea is to find a chink in the fungus’s life cycle.
Verticillium infects roots in the spring. From there, it colonizes the plant, moving through the root vascular tissue and into the stem. This is the cause of in-season vegetative wilting, Pasche noted.
As it progresses, plant cells die, leaving behind tell-tale black dots on dead tissue. Magnification of those dots reveals what look like dark bunches of grapes — tiny spheres containing melanized hyphae, a resting form of the fungus called microsclerotia.
The dark colour comes from melanin, the same pigment found in human skin. This pigmentation protects the microsclerotia from ultraviolet light.
