Remdesivir disrupts COVID-19 virus better than other similar drugs

 In the treatment of SARS-CoV-2, the virus that causes COVID-19, antiviral drug remdesivir has emerged as a promising candidate.

Remdesivir works by disrupting the virus's ability to replicate, but its exact mechanism has remained a mystery. Using advanced computational simulations, researchers at the Pritzker School of Molecular Engineering (PME) at the University of Chicago have revealed just how the drug works at the molecular level. They also found that two drugs that work in a similar manner, ribavirin and favilavir, do not bind as effectively to the virus.

"It's important to understand how remdesivir works at a molecular level," said Prof. Juan de Pablo, who led the research. "Now that we see that it is effective, and other drugs are not as effective, it can guide future efforts for treating COVID-19."

The results were published Jan. 6 in the journal ACS Central Science.

Understanding how drugs disrupt the virus

Remdesivir works by disrupting SARS-CoV-2's RNA polymerase, a key enzyme that the virus needs to replicate itself. When this enzyme is disrupted, the virus cannot multiply and spread within the body.

But in patients, the drug has produced varied results. Some clinical trials have shown that patients who received it recovered faster and had improved mortality rates, while other trials have shown that the drug did not reduce mortality or hospitalization lengths.

Since the beginning of the pandemic, de Pablo and his group have been using advanced computational simulations to systematically look at the different proteins that allow the virus to replicate or infect cells. They also have looked at the key candidate drugs that are already used to treat other diseases and could be repurposed to inhibit those processes in SARS-CoV-2. The simulations, which require months of extremely powerful computations, ultimately reveal what happens at the molecular level.

To better understand how treatments disrupt the RNA polymerase, de Pablo and his group simulated the interaction between the enzyme and three drugs that are already available, and that are meant to inhibit it: remdesivir, ribavirin, and favilavir. They found that remdesivir binds strongly to the virus, but ribavirin and favilavir do not bind as effectively. They also found that remdesivir destabilizes the virus's protein complex, also reducing its ability to replicate.

Now that simulations show that the drug should work at a molecular level, scientists could focus, for example, on finding better strategies to deliver the drug more effectively, de Pablo said.

A complete landscape of molecular targets

Previously, the group used computational analysis to reveal how the drug Ebselen binds to the virus' main protease, or MPro. Now, the group is also examining the mechanisms of a different set of drugs on different proteins, with the goal of creating a complete landscape of molecular targets.

"We've seen that the virus is not going away and is in fact starting to mutate," de Pablo said. "Efforts to find the best therapies, and the best ways to administer them, have to continue."

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Other authors on the paper include graduate students Fabian Byléhn, Walter Alvarado, and Gustavo R. Perez-Lemus, and postdoctoral researcher Cintia A. Menéndez.

Citation: "Modeling the Binding Mechanism of Remdesivir, Favilavir, and Ribavirin to SARS-CoV-2 RNA-Dependent RNA Polymerase," Byléhn et al, ACS Cent. Sci., Jan. 6., 2021. DOI: 10.1021/acscentsci.0c01242

Funding: National Science Foundation

https://www.eurekalert.org/pub_releases/2021-01/uoc-rdc012921.php

Common HIV drugs may prevent leading cause of vision loss

 Scientists have identified a group of drugs that may help stop a leading cause of vision loss after making an unexpected discovery that overturns a fundamental belief about DNA.

The drugs, known as Nucleoside Reverse Transcriptase Inhibitors, or NRTIs, are commonly used to treat HIV. The new discovery suggests that they may be useful against dry macular degeneration as well, even though a virus does not cause that sight-stealing condition.

A review of four different health insurance databases suggests that people taking these drugs have significantly reduced risk of developing dry macular degeneration, a condition that affects millions of Americans.

"We are extremely excited that the reduced risk was reproduced in all the databases, each with millions of patients," said Jayakrishna Ambati, MD, a top macular degeneration researcher at the University of Virginia School of Medicine. "This finding provides real hope in developing the first treatment for this blinding disease."

Targeting Macular Degeneration

The new discovery comes from Ambati; Fred H. Gage, Ph.D., of the Salk Institute for Biological Studies; and collaborators around the world. The work rewrites our understanding of DNA, revealing for the first time that it can be manufactured in the cytoplasm of our cells, outside the cell nucleus that is home to our genetic material.

The buildup of a certain type of DNA in the cytoplasm, Alu, contributes to macular degeneration, the researchers found. This buildup appears to kill off an important layer of cells that nourishes the retina's visual cells.

Based on this discovery, the researchers decided to look at drugs that block the production of this DNA, to see if they might help prevent vision loss. They analyzed multiple U.S. health insurance databases—encompassing more than 100 million patients over two decades—and found that people taking NRTIs were almost 40% less likely to develop dry macular degeneration.

The researchers are urging further study to determine if these drugs or safer derivatives known as Kamuvudines, both of which block a key inflammatory pathway, could help prevent vision loss from dry macular degeneration.

"A clinical trial of these inflammasome-inhibiting drugs is now warranted," said Ambati, the founding director of UVA's Center for Advanced Vision Science. "It's also fascinating how uncovering the intricate biology of genetics and combining it with big data archeology can propel insights into new medicines."

Ambati, of UVA's Department of Ophthalmology, previously determined that NRTIs may help prevent diabetes as well.

The researchers have published their findings in the scientific journal PNAS.

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Explore further

HIV drugs could prevent diabetes, study suggests

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More information: Shinichi Fukuda el al., "Cytoplasmic synthesis of endogenous Alu complementary DNA via reverse transcription and implications in age-related macular degeneration," PNAS (2021). www.pnas.org/cgi/doi/10.1073/pnas.2022751118

https://medicalxpress.com/news/2021-02-common-hiv-drugs-vision-loss.html

How defects in mitochondria may lead to autism spectrum disorder

 Researchers at Children's Hospital of Philadelphia (CHOP) have demonstrated that autism spectrum disorder (ASD) may be caused by defects in the mitochondria of brain cells. The findings were published online by the Proceedings of the National Academy of Sciences.

Multiple studies have revealed hundreds of mutations associated with autism spectrum disorder, but there is no consensus as to how these genetic changes cause the condition. Biochemical and physiological analyses have suggested that deficiencies in mitochondria, the "batteries" of the cell that produce most of the body's energy, might be a possible cause. Recent studies have shown that variants of mitochondrial DNA (mtDNA) are associated with autism spectrum disorder.

The study team hypothesized that if defects in the mitochondria do predispose patients to ASD, then a mouse model in which relevant mtDNA mutations have been introduced should present with autism endophenotypes, measurable traits similar to those seen in patients. For this model, the traits related to autism included behavioral, neurophysiological, and biochemical features.

"Autism spectrum disorder is highly genetically heterogeneous, and many of the previously identified copy number and loss of function variants could have an impact on the mitochondria," said Douglas C. Wallace, Ph.D., Director of the Center for Mitochondrial and Epigenomic Medicine and the Michael and Charles Barnett Endowed Chair in Pediatric Mitochondrial Medicine and Metabolic Diseases at CHOP, co-senior author of the study, with Eric D. Marsh, MD, Ph.D., attending pediatric neurologist, Division of Child Neurology at CHOP.

The researchers—including co-first authors Tal Yardeni, Ph.D. and Ana G. Cristancho, MD, Ph.D. - introduced a mild missense mutation in the mtDNA ND6 gene into a mouse strain. The resulting mouse exhibited impaired social interactions, increased repetitive behaviors and anxiety, all of which are common behavioral features associated with autism spectrum disorder. The researchers also noted aberrations in electroencephalograms (EEG), more seizures, and brain-region specific defects on mitochondrial function. Despite these observations, the researchers found no obvious change in the brain's anatomy. These findings suggest that mitochondrial energetic defects appear to be sufficient to cause autism.

"Our study shows that mild systemic mitochondrial defects can result in autism spectrum disorder without causing apparent neuroanatomical defects," Wallace said. "These mutations appear to cause tissue-specific brain defects. While our findings warrant further study, there is reason to believe that this could lead to better diagnosis of autism and potentially treatments directed toward mitochondrial function."

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Explore further

Autism spectrum disorder linked to mutations in some mitochondrial DNA

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More information: Tal Yardeni el al., "An mtDNA mutant mouse demonstrates that mitochondrial deficiency results in autism endophenotypes," PNAS (2021). www.pnas.org/cgi/doi/10.1073/pnas.2021429118

https://medicalxpress.com/news/2021-02-defects-mitochondria-autism-spectrum-disorder.html

Top Chinese expert Zhong Nanshan, Fauci to discuss pandemic in public

 China’s top respiratory disease expert Zhong Nanshan has said he will appear with Anthony Fauci, the US President’s chief medical adviser, at an online forum in March – the first public discussion of the Covid-19 pandemic between the two.

Zhong told a press conference after a Covid-19 control event in Guangzhou on Sunday that they “share some similar views” and would discuss the pandemic at an online event hosted by a British university.

Edinburgh University announced on its website that the two would speak at the opening session of a virtual seminar on March 2 at the Edinburgh Futures Institute.

Zhong also said he will discuss the pandemic with experts from Harvard Medical School next week.

“If there is a turning point in the US pandemic, it would be great news for the whole world,” said Zhong, acknowledging that the Biden administration has made fighting the pandemic one of its top priorities.

The US, which has the world’s highest death toll from Covid-19, has seen more than 26 million cases and over 438,000 deaths, according to Johns Hopkins University.

China-US tensions have escalated since the start of the global outbreak, with the two sides trading barbs over the origins of the coronavirus and Donald Trump accusing Beijing of failing to contain the disease at the start.

Beijing has urged the new US administration to cooperate in fighting the pandemic as part of efforts to ease tensions between the two sides.

Although China has largely been successful in fighting the disease, it has recently seen a spike in cases across the country. The National Health Commission said on Sunday that January had seen 2,016 domestic cases, the highest number since March.

The country reported 73 new confirmed cases of infection on Saturday, all from the north and northeastern provinces of Hebei, Jilin and Heilongjiang – up from 36 confirmed cases on Friday.

Zhong said: “I think the situation in these three locations will be brought under control in February,” adding that strict prevention measures should reduce the infection rate by 20 to 30 per cent.

However, Zhong still advised people to stay put and reduce gatherings during the Lunar New Year, which starts on February 12, to prevent the situation from worsening again.

Meanwhile, Xu Wenbo, director of the National Institute for Viral Disease Control and Prevention, told a National Health Commission briefing that more than 24 million doses of the Covid-19 vaccine have been administered in China so far.

He added the number of serious abnormal reactions reported was no higher than for flu vaccines.

https://www.scmp.com/news/china/diplomacy/article/3119986/coronavirus-top-chinese-expert-zhong-nanshan-and-us

Robust spike antibody responses, increased reactogenicity in seropositive individuals after single dose of SARS-CoV-2 mRNA vax

 Florian Krammer1$, Komal Srivastava1 , the PARIS team1*, and Viviana Simon1,2,3

 doi: https://doi.org/10.1101/2021.01.29.21250653

Abstract 

An important question is arising as COVID-19 vaccines are getting rolled out: Should individuals who already had a SARS-CoV-2 infection receive one or two shots of the currently authorized mRNA vaccines. In this short report, we show that the antibody response to the first vaccine dose in individuals with pre-existing immunity is equal to or even exceeds the titers found in naïve individuals after the second dose. We also show that the reactogenicity is significantly higher in individuals who have been infected with SARS-CoV-2 in the past. Changing the policy to give these individuals only one dose of vaccine would not negatively impact on their antibody titers, spare them from unnecessary pain and free up many urgently needed vaccine doses.

https://www.medrxiv.org/content/10.1101/2021.01.29.21250653v1.full.pdf

Single Dose Vaccination in Healthcare Workers Previously Infected with SARS-CoV-2

 Saman Saadat,  

View ORCID ProfileZahra Rikhtegaran-Tehrani,  View ORCID ProfileJames Logue, Michelle Newman,  View ORCID ProfileMatthew B Frieman, Anthony D. Harris,  View ORCID ProfileMohammad M. Sajadi

doi: https://doi.org/10.1101/2021.01.30.21250843

This article is a preprint and has not been certified by peer review [what does this mean?]. It reports new medical research that has yet to be evaluated and so should not be used to guide clinical practice.

PDF: https://www.medrxiv.org/content/10.1101/2021.01.30.21250843v1.full.pdf

Abstract

Coronavirus disease 2019 (COVID-19) vaccine shortages have led some experts and countries to consider untested dosing regimens. We studied antibody responses to a single dose of the Pfizer-BioNTech or Moderna vaccines in healthcare workers (HCW) with laboratory-confirmed COVID-19 infection and compared to them to antibody responses of HCW who were IgG negative to SARS-CoV-2 spike protein. HCW with prior COVID-19 showed clear secondary antibody responses to vaccination with IgG spike binding titers rapidly increasing by 7 days and peaking by days 10 and 14 post-vaccination. At all time points tested, HCW with prior COVID-19 infection showed statistically significant higher antibody titers of binding and functional antibody compared to HCW without prior COVID-19 infection (p<.0001for each of the time points tested). In times of vaccine shortage, and until correlates of protection are identified, our findings preliminarily suggest the following strategy as more evidence-based: a) a single dose of vaccine for patients already having had laboratory-confirmed COVID-19; and b) patients who have had laboratory-confirmed COVID-19 can be placed lower on the vaccination priority list.

Competing Interest Statement

The authors have declared no competing interest.

Funding Statement

ADH supported by CDC grant U01CK000556-02-01.

https://www.medrxiv.org/content/10.1101/2021.01.30.21250843v1

Fresenius sees significant negative impact on 2021 net income due to Covid impact

 Fresenius Medical Care AG & Co. KGaA anticipates significant negative impact on 2021 net income due to accelerated

impact of Covid-19 related excess mortality on its patient population 
Based on preliminary numbers Fresenius Medical Care confirms achievement of its 2020 financial targets, with net income 
(attributable to shareholders of Fresenius Medical Care AG & Co. KGaA) slightly above the top end of the target range. 
Earnings development was impacted negatively in Q4 by an impairment in the Latin America segment of approximately EUR 
195 million, which is treated as a special item. 
Fresenius Medical Care hereby informs the market early on its indicative preliminary assumptions for the development of 
the net income in fiscal year 2021. 
The significant acceleration in November and December 2020 of Covid-19 related patient excess mortality is expected to 
continue into 2021. In addition, the Company anticipates the associated cost for safety measures for patients and 
employees to remain at a high level. Fresenius Medical Care continues to monitor the further development of mortality, 
the adoption and speed of roll out of vaccinations as well as government relief measures and to closely evaluate 
opportunities to adjust its cost base. 
Against this backdrop, Fresenius Medical Care anticipates, based on early indications and before special items, such as 
potential restructuring measures, and on a constant currency basis, revenue growth of up to mid-single digits and 
assumes net income (attributable to shareholders of Fresenius Medical Care AG & Co. KGaA) to decline by up to 25 
percent. 

https://www.marketscreener.com/quote/stock/FRESENIUS-MEDICAL-CARE-AG-436087/news/DGAP-Adhoc-Fresenius-Medical-Care-AG-Co-KGaA-anticipates-significant-negative-impact-on-2021-ne-32330261/