A collaboration led by Scripps Research has developed a way to separate the beneficial anti-inflammatory properties of a group of steroids called glucocorticoids from some of their unwanted side-effects, through an optimization process they named “ligand class analysis.”
Their process enabled them to engineer two new, drug-like compounds that show steroidal anti-inflammatory action and other specific traits. One boosts muscle and energy supply, while the other reduces risk of muscle-wasting and bone loss typical of such drugs.
Their report, titled, “Chemical systems biology reveals mechanisms of glucocorticoid receptor signaling,” appeared Jan. 28 in the journal Nature Chemical Biology.
Glucocorticoids are steroid hormones, a group that includes cortisone, prednisone and dexamethasone. Among the most frequently prescribed of medications, their anti-inflammatory properties make them useful in an array of forms and doses.
Glucocorticoids are used as injections for hip or back pain, tablets for autoimmune disease, nasal spray for sinus congestion, anti-itch cremes for soothing rashes or insect bites, and more.
But glucocorticoids are also among the more problematic of medicines, as prolonged use or high doses can lead to adverse events including high blood pressure, muscle wasting, bone loss, vulnerability to infections, vision problems, anxiety, swelling, weight gain, high blood sugar, insulin resistance, diabetes, and more, while naturally occurring glucocorticoids in the body can contribute to prostate cancer progression.
Pursuing safety
A key goal of the team was to engineer more precise glucocorticoids able to act in tissue-specific or activity-specific way, while limiting specific adverse events, says the study’s lead author, Kendall Nettles, Ph.D., associate professor of Integrative and Structural Biology at the Scripps Research, Florida campus.
“There is a great unmet need to improve glucocorticoids,” Nettles says. “We asked, ‘Can we develop glucocorticoids that have more selective effects on inflammation and the immune system, instead of hitting the body with a hammer?’ This method is showing that we can do that now.”
The project pooled the expertise of many collaborators, in areas including chemistry, bioinformatics, structural biology, proteomics, genomics, cell metabolism and more. Contributors included Scripps Research, Florida-based faculty and their scientific staff and students; a researcher from the institute’s California-based drug discovery division, Calibr, and scientists from Weill Cornell Medicine, Emory University School of Medicine, the National Cancer Institute and others.
Nettles says their “ligand class analysis” process began with selection of a known corticosteroid compound. Scripps Research chemist Theodore Kamenecka, Ph.D., modified the compound in many ways to build a collection of new molecules.
One substitution at a time, the scientists created 22 new compounds that showed an ability to actively bind with cell receptors for steroids. They then devised an experimental platform for testing precisely how these compounds affected muscle, bone and lung cells, to indicate each one’s risk of causing muscle loss or bone loss, while keeping anti-inflammatory activity.
One of the greatest challenges they encountered was devising a way to accurately test the molecules in cultured cells, Nettles says. At first, they seemed to require 1,000 times more compound than expected to measure impact.
Stress produces results
First author Nelson Bruno had the breakthrough idea of testing only after stress, specifically, fasting followed by brief insulin challenge. That’s because stress is the trigger for release of endogenous steroid hormones in real life, Nettles explains.
“It took us two years just to develop the experimental assays to reproduce the effects of what glucocorticoids do in people,” Nettles says. “We found we needed realistic physiology.”
They also used a machine learning approach to predict how the compounds would affect insulin receptor signaling, gene transcription, protein balance and glucose disposal in the cells, depending on chemical structure.
Through repeated challenges and tests in the cells and in mice, they settled on two compounds, SR11466 and SR16024, as ones with medically useful traits including inflammation control, plus muscle-sparing ability, or mitochondria-building potential. Mitochondria convert cellular nutrients into energy.
The process they developed to refine the compounds has implications well beyond the improvement of glucocorticoids, Nettles adds. It can power more-selective drug-discovery for any number of medicines that work via the cell surface and nuclear receptors to impact signaling and gene transcription in cells, he says.
This project started long before the COVID-19 pandemic began, Nettles says, but it has potential to benefit people sickened with COVID-19. In the context of an infectious disease, the ideal anti-inflammatory would be one that suppressed overly aggressive immune attack without impairing ability to fight off infection, so that’s the next goal, he says. More work is needed to address bone loss risk as well, he says.
“These drugs could be used more widely if we could reduce the side-effects profile,” Nettles says. “We brought together many recent scientific advances to address a significant problem that affects huge numbers of people.
Our findings show that using ligand class analysis, we can potentially improve the safety and specificity of steroids and other needed medicines.”
An infectious disease caused by a previously unknown type of coronavirus, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), emerged at the end of December 2019 and has posed a major challenge to the public health worldwide (1). The World Health Organization (WHO) officially named the disease as Coronavirus Disease 2019 (COVID-19) on February 11, 2020 (2). On March 11, 2020, the WHO declared COVID-19 as a global pandemic (3). Globally, as of 2:00 am CEST, 12 April 2020, there have been 1,699,595 confirmed cases of COVID-19, including 106,138 deaths, reported to WHO (4).
At present, there are no specific drugs for the prevention and treatment of COVID-19, and symptomatic supportive treatment remains the most effective method of care. Full-genome sequencing and phylogenetic analyses have indicated SARS-CoV-2 is a distinct clade of beta-coronaviruses, related to the Middle East respiratory syndrome coronavirus (MERS-CoV) and SARS-CoV. Therefore, the management of COVID-19 can benefit from experience from the SARS and MERS epidemics (5). Glucocorticoids were commonly used for the treatment of SARS and MERS especially in critically ill people (6,7), and are also widely used in the treatment of COVID-19.
There are conflicting opinions about the use of glucocorticoids to treat patients with COVID-19. It is suggested that current clinical evidence does not support the use of glucocorticoids, which may cause several side effects (8,9). However, clinicians who are on the front line of the epidemic have proposed that short-term glucocorticoid therapy with small or medium dose could be beneficial for patients with severe conditions (10).
The current guidelines on COVID-19 are also inconsistent about the use of glucocorticoids. Some guidelines suggested trying short-term therapy with medium or small doses of glucocorticoids for patients with rapid or severe disease progression, but according to the WHO guidelines glucocorticoids should only be used under clinical trial conditions (11-13). Effective evidence related to glucocorticoi1ds to treat COVID-19 is still lacking.
Discussion
Our study identified direct evidence on the clinical efficacy of glucocorticoid therapy for five difference outcomes in adults with COVID-19. Evidence of low to very low-quality showed that glucocorticoid therapy significantly reduced the duration of fever, but not the risk of death and lung inflammation absorption in patients with COVID-19 or SARS.
In addition, glucocorticoid therapy may even prolong the duration of hospitalization. Long-term use of high-dose glucocorticoids increased the risk of adverse reactions such as infections and osteonecrosis. We found moderate-quality evidence that in patients with mild SARS glucocorticoids may be associated with a more than three-fold increase in the risk of death.
Systemic glucocorticoids are highly effective anti-inflammatory drugs, but their use against SARS-CoV-2 infection remains controversial. A case series of children with COVID-19 reported that systematic glucocorticoids (dose 2 mg/kg) were given to both two included critical cases in combination with invasive mechanical ventilation and intravenous immunoglobulin. In both children, the symptoms on admission were alleviated, although in one of them only partly (52).
A recent cohort study from JAMA Internal Medicine reported that among COVID-19 patients with ARDS, treatment with methylprednisolone decreased the risk of death (39). Our results are compared with published systematic reviews of glucocorticoid therapy for severe pneumonia. A recent rapid review of COVID-19 treatment showed controversial evidence on the use of corticosteroids, and could not give any suggestion on the use of corticosteroids due to the lack of quantitative synthesis (53).
A systematic review covering in vitro studies on SARS, SARS in humans and other diseases such as ARDS, found that 25 of the 29 included studies were inconclusive, and the remaining four found glucocorticoids harmful (54). A recent systematic review of influenza pneumonia showed that glucocorticoid therapy increased the risk of death (RR =1.75, 95% CI: 1.30, 2.36), length of ICU stay (RR =2.14 days, 95% CI: 1.17, 3.10), and risk of secondary infections (RR =1.98, 95% CI: 1.04, 3.78) (55).
A meta-analysis of SARS in 2017 showed that the incidence of osteonecrosis increased with the dosing of systemic glucocorticoids, and the summary RR of osteonecrosis was 1.57 (95% CI 1.30, 1.89) (56). As retrospective studies have shown that the glucocorticoids were given for 19% to 26% of patients with COVID-19 (and to 45% of patients with severe disease), there is a high risk that this therapy is currently misused (57-59).
In summary, the current research evidence does not support the routine use of systemic glucocorticoids for patients with COVID-19. Because COVID-19 tends to be less severe in children than in adults (60), the use of systemic glucocorticoids should in particular not be recommended in children.
reference link:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7290628/
More information: Nelson E. Bruno et al, Chemical systems biology reveals mechanisms of glucocorticoid receptor signaling, Nature Chemical Biology (2021). DOI: 10.1038/s41589-020-00719-w
