Clinical Evaluation of LeSoleil Against COVID-19
Announcement on Global Recruitment of Collaborative Agencies for LeSoleil
Since February 2020, Suntrap Life Technologies Ltd. has prudently evaluated and predicted the characteristics of COVID-19. A Suntrap research team was immediately established and the project for the drug discovery against COVID-19 was launched. Utilizing the self-built S-CPDD drug design and discovery system and IDDNU® (International Drug Design Network Union) platforms that are constructed in accordance with scientific laws of drug discovery , Suntrap's research team fully tracked and analyzed the pathological characteristics, clinical needs, pathogenesis research and social demands of patients. In terms of the determination of the direction of drug research and development (R&D), COVID-19 drug related targets acquisition, molecular design and screening, and preclinical verification, the new drug R&D in the Suntrap research team is fully guided by clinical values. It will be a standard for the Suntrap team that can quickly transform biomedical research into industrial products , and ultimately develop new pharmaceutical products that benefit the public, thus realizing the fundamental significance of new drug R&D.
Suntrap's team believes that the prevention and treatment of COVID-19 should focus on the development of multi-targeted and broad-spectrum anti-coronavirus drugs.
An AI-assisted drug design module in the self-developed IDDNU® platform was employed to balance the interactions among SARS-CoV-2 related drug targets. In addition, various virtual screening modules including ADMET (drug absorption, distribution, metabolism, excretion, and toxicity) properties prediction, targets and SARS-CoV-2 infection cell model-based inhibition activity prediction were combined to screen Suntrap's self-built clinical and drug-related data resource library, and then quickly select potential compounds with good anti-COVID-19 activity and low toxicity. These potential molecules were then subjected to cell-based phenotypic antiviral screening testing.
In May 2020, the Suntrap research team identified a lead compound "LeSoleil-T" through a series of bioassays, which showed anti-coronavirus activities with multi-targets inhibition effects. Further studies revealed that the multi-targets design properties of LeSoleil-T could meet the demands of broad-spectrum anti-coronavirus.
In August 2020, the Guangdong Provincial Institute of Public Health (also known as Guangdong Provincial Center for Disease Control and Prevention) was commissioned to investigate the sensitivity of SARS-CoV-2 to "LeSoleil-T (莱素理)". The results showed that (1) LeSoleil-T has low toxicity with a TC50 value of 121.06 μg/mL; (2) LeSoleil-T showed a 99.41% inhibition on SARS-CoV-2 virus at a concentration of 121.06 μg/mL; and (3) a high inhibitory effect on SARS-CoV-2 (> 63.06%) can be achieved at ultra-low concentrations (0.195~1.562 μg/mL). In the stage of demonstrating the relationship between toxicity, dosage, and biological efficacy, the experimental results of the rat model showed that the LD50 of LeSoleil-T is greater than 5 g/kg, indicating that LeSoleil-T has high safety at the animal level.
To clarify the pharmacological function of LeSoleil-T against COVID-19, the Suntrap research team conducted systematic analysis of the infection mechanisms of SARS-CoV-2. Previous studies have shown that SARS-CoV-2 virus infects human cells through two major routes: endocytic and non-endocytic routes. Commonality is presented in these two infectious processes. Both of them activate the spike protein of SARS-CoV-2 through the TMPRSS2 protease of the host cell. Subsequently, the spike protein binds to ACE2 receptor protein on the surface of the host cell, to allow the virus or its nucleic acid to enter the host cell, and the SARS-CoV-2 is finally replicated with the help of the Mpro protein.
SARS-CoV-2 viruses enter the oral and nasal cavity through the respiratory tract. The mucosa of the nasal/oral cavity provides surfaces for the direct contact area with air. In addition, the ACE2 receptor protein is highly expressed on nasal mucosal cells. Therefore, the oral pharynx and nasal cavity are easily infected by SARS-CoV-2 virus. The viruses will enter the sinuses through the nasal cavity after infecting the cells in the nasal cavity. There are four cavities around the sinuses: frontal sinus, sphenoid sinus, ethmoid sinus and maxillary sinus. All of the sinuses are connected to the nasal cavity. SARS-CoV-2 can hide in these four cavities and will be released after massive replication. In addition, SARS-CoV-2 viruses can easily bind to sialic acid to avoid being detected by the human immune system.
A series of cascade reactions in lung can be triggered by a variety of cytokines and chemotactic factors after the large number of SARS-CoV-2 replication in the oral and nasal cavity and its entering into lung through the pharyngeal respiratory tract, which results in severe lung inflammation and pathology. The virus causes damage to lung tissue, where lung atrophy and pulmonary edema can occur, affecting the body's exchange of oxygen and resulting in acute respiratory distress, which contribute to the leading cause of death for many severely infected patients. After entering the lung, SARS-CoV-2 spreads rapidly in the human body, resulting in systemic infection and illnesses, including viral infection, lung inflammation, gastrointestinal dysfunction, and damages to the central nervous system, peripheral nervous system, myocardial fibers and myocardial cells, liver and kidney tissues, as well as muscle tissues.
In view of the inhibitory effects of LeSoleil-T against SARS-CoV-2, the pharmacological mechanisms of LeSoleil-T were explored through a series of experimental assays. The results showed that LeSoleil-T has pharmacological effects in the treatment of SARS-CoV-2 infection as the following: broad-spectrum anti-coronavirus inhibitory effects, anti-inflammatory effects, neuron protections, delay and reversal of tissue fibrosis.
Based on the above results, the Suntrap team has obtained the Chinese invention patent authorization for the broad-spectrum anti-coronavirus in January 2021, and has filed international patent applications through the PCT, and applied for patent protection in many countries and regions.
Suntrap’s research team found that LeSoleil-T exerts effects against SARS-CoV-2 through directly inhibition of the activity of TMPRSS2 and Mpro (also known as 3CLpro). As known, TMPRSS2 and Mpro are involved in SARS-CoV-2 replication and infection. For one thing, LeSoleil-T inhibits the activation of spike protein by TMPRSS2 and blocks the entry of the SARS-CoV-2 virus into the host cell. For another, it inhibits the Mpro of SARS-CoV-2 to suppress its replication. In addition, Mpro exists in various coronaviruses, which contribute to the broad-spectrum anti-coronavirus characteristic of LeSoleil-T by its inhibition of Mpro protein.
According to clinical investigations, upon SARS-CoV-2 infection, the levels of the neutrophil count, D-dimer, blood urea and creatinine in patients will increase continuously, while the count of lymphocytes will continue to decline until death. Suntrap team found that LeSoleil-T could eliminate inflammation induced by SARS-CoV-2 infection. The anti-inflammatory effects of LeSoleil-T are mainly to inhibit proinflammatory factor expression and reduce oxidative stress responses. Firstly, LeSoleil-T can inhibit neutrophil aggregation to reduce the production of 4-HNE (4-hydroxynonenal) by oxidative stress response, which leads to the reduction of the lipid peroxidation end-product formation, and finally, contribute to its anti-inflammatory activity. Secondly, LeSoleil-T directly inhibits the expression of proinflammatory factors (e.g., Tnf-α, IL-1β, IL-6, Mcp-1, Mcp-2, and Mip-1α). Finally, it activates the interactions among PGC-1α (Peroxisome proliferator-activated receptor-γ coactivator), Nrf1 (Nuclear Respiratory Factor 1) and Nrf2 (Nuclear Respiratory Factor 2) to regulate the mitochondrial synthesis, respiration, and various antioxidant enzymes. Meanwhile, the Nrf2/ARE (antioxidant response element) complex scavenges free radicals by regulating the expression of HO-1 (heme oxygenase-1).
According to the clinical studies on COVID-19, the sequelae caused by SARS-CoV-2 infection include nervous system damage, pneumonia-induced lung fibrosis, cardiomyocyte damage, liver and kidney damage. In response to the nervous system damage caused by SARS-CoV-2, LeSoleil-T showed neuroprotective effects by regulating the expression of related proteins and reducing the stress response. Detailed mechanisms are as follows: (1) It can reduce inflammatory to prevent cell damage and protect neurons; (2) LeSoleil-T can activate NF-κB (Nuclear factor kappa B) to inhibit the inflammation of microglia and the proliferation of microglia and astrocytes to protect neurons; (3) LeSoleil-T can protect neurons by inhibiting the expression of c-fos and c-jun, and regulating the expression of Bax (pro apoptotic factor), Bcl-2 (inhibitor of apoptosis) and caspase-3 (terminal shear enzyme of apoptosis); and (4) LeSoleil-T can reconstruct the expression of Akt and pAkt in the cerebral cortex, to maintain the levels of Akt and pAkt, and to promote neuronal survival.
In terms of pulmonary fibrosis caused by COVID-19, the Suntrap research team uncovered that LeSoleil-T can reduce the protein expression of iNOS (Inducible nitric oxide synthase) in vivo and in vitro, resulting in reducing the combination of NO and free radicals to form RNS, the stress reaction of the nitro, lung injury, and pulmonary fibrosis. Besides, LeSoleil-T can inhibit TGF-β1-mediated EMT (Epithelial-mesenchymal transition) signaling pathway and reduce the phosphorylation of SMAD2/3, decrease ERK1/2 (extracellular signal-regulated kinase) and activate the SMAD signal , the protein expression of Coll and Timp, upregulate the expression of MMP (matrix metalloproteinase), reduce the expression of ECM (extracellular matrix), prevent the ECM from accumulating excessively, reduce myofibroblast formation, repair the damaged tissue, delay and reverse pulmonary fibrosis.
Based on the clinical symptoms and pathogenic mechanism of patients infected with SARS-CoV-2, the Suntrap's research team optimized and developed different clinical protocols. The basic formulation was completed in November 2020.
LeSoleil the broad-spectrum anti-COVID-19 protective and therapeutic spray include three types: LeSoleil-01, oral spray; LeSoleil-02, nasal spray; and LeSoleil-02+, preventive and therapeutic ultrasonic atomizing inhaler. The broad-spectrum anti-COVID-19 protective and therapeutic spray is suitable for COVID-19 protection and patients with asymptomatic or mild infection. LeSoleil-03 is a therapeutic "anti-COVID-19 aerosol inhaler", which is suitable for patients with moderate and severe SARS-CoV-2 infection. In addition, LeSoleil-03 can also be used in patients with pulmonary fibrosis sequelae caused by SARS-CoV-2 infection. All of these three preparations are suitable for children, adults and the elderly.
The LeSoleil broad-spectrum anti-coronavirus protective and therapeutic spray is portable and easy to use. It effectively prevents healthy people from infection and blocks the spread of SARS-CoV-2 from asymptomatic and mild COVID-19 patients. LeSoleil broad-spectrum anti-coronavirus protective and therapeutic spray can cope with the prevention and treatment of SARS-CoV-2 and variant strains (e.g., Delta and Omicron.). In addition, the preclinical study conducted by the Suntrap team revealed that LeSoleil can also be used for upper respiratory tract infections caused by influenza viruses and mutant strains (e.g., H1N1, H5N1, H7N1, H7N2, H7N3, H7N7, H7N9, H9N2 and H10N8). The new corresponding symptoms still need to be verified by clinical research.
The characteristics of LeSoleil broad-spectrum anti-coronavirus protective and therapeutic spray are as follows: (1) it can inhibit virus replication, control the virus load in the mouth and nose, and reduce the probability of aggravation; (2) it inhibits the combination of SARS-CoV-2 and sialic acid, and then helps the human immune system to recognize the viruses; (3) LeSoleil-T is positively charged and can effectively adsorb negatively charged SARS-CoV-2 virus, so as to inhibit the transfer of viruses in host cells; (4) it can inhibit the production of pro-inflammatory factors to inhibit inflammation, and effectively treat upper respiratory tract inflammation and other related symptoms caused by COVID-19; (5) it has a dynamic consistency similar to that of the mucus of the oral cavity and nasal cavity, which can make the broad-spectrum anti-coronavirus protective and therapeutic spray evenly adhere to the mucous membrane after reaching the oral cavity and nasal cavity, forming a "biological protective film" that lasts for a long time. For some asymptomatic or mildly infected people, a small amount of the virus will be excreted when they cough, sneeze or exhale. After using a broad-spectrum anti-coronavirus protective and therapeutic spray, the active ingredient LeSoleil-T can inhibit the excreted virus and block the route of virus transmission to achieve a more extensive protective effect.
For patients with moderate and severe SARS-CoV-2 infections, it is recommended to use LeSoleil-03 twice a day to treat the infection and inflammation in the respiratory tract and lungs. It is convenient for patients to use, including dissolving LeSoleil-03 in sterile water and then inhaling through the respiratory tract directly to the lungs via a ventilator and medical atomizing device. The characteristics and efficacies of LeSoleil-03 are as follows: (1) it has a small particle size and no foreign body sensation, and it is easy to inhale with medical machinery or a small medical-grade ultrasonic atomization device and reach the lungs through the bronchus to avoid the first-pass effect; (2) the local drug concentration is high, and it takes effects quickly to inhibit the replication of the virus, eliminates inflammation of the respiratory tract and lungs, slows down breathing difficulties, and quickly excretes sputum to relieve symptoms; (3) it can reduce lung inflammation and oxidative stress, prevent cell damage that leads to the formation of myofibroblasts, and postpone tissue fibrosis; (4) it can regulate the expression of pro-apoptotic factors and apoptosis-inhibiting factors, repair damaged lung tissue, and reverse tissue fibrosis.
Currently, in-depth verifications of the sequelae of the SARS-CoV-2 infection (e.g., loss of taste, central nervous system, and peripheral nervous system damage) are still in progress.
The pandemic of COVID-19 has been lasting for nearly two years. Its mutant strains are constantly emerging, and the global incidence rate continues to rise. To date, Suntrap research team has made a certain degree of a breakthrough in the design of multi-target anti-coronavirus drugs. It is necessary to accelerate the clinical verification and strengthen cooperation. To conduct more in-depth clinical research for LeSoleil莱素理® anti-SARS-CoV-2 drugs, and make COVID-19 not to be an obstacle for social stability, economic development and human health, Suntrap recruits qualified clinical research institutions around the world to carry out clinical revalidation studies on the efficacy of the LeSoleil莱素理® broad-spectrum anti-coronavirus series of drugs against their known mutant strains from SARS-CoV-2.
Consult www.suntrap.com or search for "IDDNU" and "suntrap" to find related reports.
Suntrap Life Technologies Ltd.
Suntrap Health & Environment Research Institute