Translational Research On COVID
Research On Covid 19
Covid as a pandemic has created significant morbidity and mortality asking for a solution. Atrimed Pharmaceuticals, being specialized in drug development based on plant based molecules, has a systematic approach for drug development. The steps include target identification, Lead generation, lead optimization, ligand target binding in silico studies, MD Simulation, in vitro studies, in vivo studies and human trials.
spike glycoprotein, RdRp, 3CLPro, PLPro,E-Protein and M-Protein are the drug targets which have been identified and worked upon. Understanding of plant chemistry and computational chemistry takes significant role in lead generation. Since we have a library of plant molecules, initial screening is done by looking for simulation studies for target ligand binding. Lead optimization is carried out by making changes at chemical moieties to simplify the synthesis, reduce the size or improve the binding. Subsequent retrospective similarity search can identify the potential plants. A poly pharmacology approach to identify a molecule for multiple targets or, multiple molecules in single plant towards same or multiple targets or multiple molecules in multiple plants for different or same targets are some of the strategies to be adopted. All these strategies need to be reconfirmed in in vitro as well as in vivo experiments before trying them in human beings.
Through good understanding of medicinal chemistry, analytical chemistry and Synthesis, team of chemists can contribute for getting physical samples for experiments.
Thus a translational work between traditional medicine practitioners, computation biologists, medicinal chemists, synthetic chemists, Microbiologists/Molecular biologists/Biotechnologists, veterinarians/Animal pharmacologists, and finally clinical pharmacologists leads to drug development at Atrimed Pharmaceuticals. The drug development for Covid is currently at Phase-1 and will resume to Phase 2 & 3 soon.
COVID-19, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), currently has a detrimental impact on human health, community, and the economy. SARS-CoV-2-infected lung +ssue ini+ally fails to induce a range of immune cell-recrui+ng molecules, including several interferons, sugges+ng that leukocytes are ineffec+vely recruited to infected lung shortly after infec+on. The host cell entry receptor ACE2 has been iden+fied as an interferon target gene. Thus, even when interferons are upregulated, upregula+on of ACE2 expression may aggravate infec+on. These observa+ons suggest that baseline levels of leukocytes, already present/ growing in the lung prior to infec+on, may be important in coordina+ng an effec+ve early immune response. The baseline expression levels of the SARS-CoV-2 host cell entry receptor ACE2 and the levels of seven types of leukocytes (involved in triggering an acute an+-viral cellular immune response) were inves+gated in 1,927 human lung +ssue samples by “in silico flow cytometry". Baseline levels of CD8+ T cells, res+ng natural killer (NK) cells, and ac+vated NK cells are significantly lower in lung +ssues with high expression of the SARS-CoV-2 host cell entry receptor ACE2. Reduced CD8+ T cell counts also predict poor COVID-19 pa+ent survival. Elevated ACE2 expression increases sensi+vity to coronavirus infec+on, accompanied by a lower ability to mount a rapid innate immune response at early stages. Finally, it may contribute to the substan+al varia+on in COVID-19 clinical presenta+on, ranging from asymptoma+c to severe respiratory and other symptoms.
Antivirals act in many ways to eliminate a virus, one of them being, blocking the interaction of the virus with host cells. One such interaction is initiated by Haemagglutinin-esterases (HEs). They are a group of viral envelope proteins that can cause the reversible attachment of the virus to host cells. HEs occur in influenza C, toro-, and coronaviruses, including SARS-CoV-2. A study of the crystal structure formed by the fusion of HE with host proteins was performed to show exactly how the HE binds to the host cell. It was found that in SARS-CoV-2, the HE-host protein binding causes the molecules to undergo radical steric changes and adopt opposite orientations leading to strong binding. This means, the virus can bind very strongly to the host cell and it cannot be easily detached again. But molecules can be developed/synthesized, that can block this interaction and thus prevent the virus from attaching to host cells so strongly. This will prevent viral RNA from entering the host cell and causing infection. This opens up potential avenues for the development of broad-spectrum antiviral drugs that can not only help with SARS-CoV-2 but also with other viruses that have similar HE-host cell interactions.
Currently, treatment options for COVID-19 remain limited, with the only evidence-based therapies being remdesivir and dexamethasone. Despite the use of these therapies, clinical outcomes remain dismal. Few recent trials emphasised that the inhaled route could provide better antiviral outcomes, as it enables maximal delivery of the active drug to the biological focus of SARS-CoV-2 infection, the respiratory epithelium, aka, the lungs. In a clinical trial, the safety and efficacy of an inhaled anti-inflammatory molecule, was investigated, in COVID-19 patients. Previous studies established that the molecule, called SNG001 was well tolerated in patients with asthma and COPD. This study showed that SNG001 seems to be well tolerated in COVID-19 patients and is associated with improvement and rapid recovery. Thus, treating patients admitted to hospital with COVID-19, with SNG001 should be explored further in a phase 3 trial to establish the timing of this treatment in critically ill patients with COVID-19 who have evidence of active viral infection in the lungs.
The virus that causes the current COVID-19 pandemic, SARS-CoV2, is a single stranded positive sense RNA virus that is closely related to severe acute respiratory syndrome corona virus (SARS-CoV). A drug developed against SARS-CoV, called Ivermectin, is a drug that can inhibit the transport of viral components to the host nucleus, thus preventing virus replication. As the viruses are very similar, it may well be effective against SARS-CoV-2. Human cells were infected with SARS-CoV-2 and treated with Ivermectin to find that it cleared all virus by 48 h. No toxicity of ivermectin was observed. It was also determined that ivermectin has antiviral action against the SARS-CoV-2 clinical isolate (in vitro), with a single dose able to control viral replication within 24–48 h in our system. This raises the possibility that ivermectin could be a useful antiviral to limit SARS-CoV-2, and is worthy of further consideration as a possible SARS-CoV-2 antiviral drug for further trial.
Effective antiviral agents are needed to treat severe acute respiratory syndrome-associated coronavirus-2 (SARS-CoV-2)infection. Interferons, alone or in combination with other interventions, are partly effective against animal coronaviruses, mouse hepatitis virus, and transmissible gastroenteritis virus; a few data on human studies report a limited response of interferon by the intranasal route. A study performed recently, assessed the antiviral potential of recombinant interferons against two clinical isolates, from Frankfurt and Hong Kong patients, replicated in human cells in the lablab. Interferon β was five to ten times more effective in neutralizing the virus. Interferon α effectively inhibited SARS-CoV-2 replication, but with a selectivity index 50–90 times lower than that for interferon β. Interferon γ was slightly better than interferon α in some human cell cultures, but was completely ineffective in other human cell cultures. Results showed that interferons inhibit SARS-CoV-2 replication in vitro. Interferon β was most potent, showing prophylactic or preventive protection as well as antiviral or curative potential after infection. Interferon β could be the drug of choice, alone or in combination with other antiviral drugs, in the treatment of COVID-19.
The outbreak of SARS-CoV-2 warrants the search for antiviral compounds to treat the disease. At present, no specific treatment has been identified for the infection. The antiviral potential of glycyrrhizin against two clinical isolates of SARS-CoV-2 was assessed and found to be highly potent, with a selectivity index of 67. Additionally, glycyrrhizin inhibits adsorption and penetration of the virus by the host cell. The mechanism of glycyrrhizin's activity against SARS-CV is unclear. Glycyrrhizin affects cellular signaling pathways such as protein kinase C and nuclear factor NFκB. Preliminary results show that glycyrrhizin inhibits virus replication and has previously been used to treat patients with HIV-1 and chronic hepatitis C virus. Infrequent side-effects such as raised blood pressure and hypokalemia were reported in some patients after several months of glycyrrhizin treatment. Treatment of SARS-CoV-2 should only be needed for a short time. Since the side-effects of this compound are known and can be controlled, proper monitoring could lead to effective use of glycyrrhizin as a treatment for SARS-CoV-2. Even when high doses of glycyrrhizin were used in clinical trials, this compound had very few toxic effects and the drug was reported to be clinically effective. Future research is required before it can be used as a potential therapy against SARS-CoV-2.
There are currently no registered therapies for treating SARS-CoV-2 infections. Because of the time consuming process of new drug development, drug repositioning may be the only solution to the epidemic of sudden infectious diseases. A recent study systematically analysed all the proteins encoded by SARS-CoV-2 genes, compared them with proteins from other corona viruses, predicted their structures, and built 19 structures by homology modelling. By performing target-based virtual ligand screening, a total of 21 targets were screened against compound libraries including ZINC drug database and their own database of natural products. Structure and screening results of important targets such as 3-chymotrypsin-like protease (3CLpro), Spike, RNA-dependent RNA polymerase (RdRp), and papain like protease (PLpro) were discussed in detail. In addition, a database of 78 commonly used anti-viral drugs including those currently on the market and undergoing clinical trials for SARS-CoV-2 was constructed. Possible targets of these compounds and potential drugs acting on a certain target were predicted. This study provides new lead compounds and targets for further in vitro and in vivo studies of SARS-CoV-2, new insights for those drugs currently ongoing clinical studies, and also possible new strategies for drug repositioning to treat SARS-CoV-2 infections.
The pandemic of COVID-19 has posed an unprecedented threat to global public health. However, the interplay between the viral pathogen of COVID-19, SARS-CoV-2, and host innate immunity is poorly understood. A recent study showed that SARS-CoV-2 induces strong but delayed type-I interferon (IFN) responses. By screening 23 viral proteins, it was found that SARS-CoV-2 NSP1, NSP3, NSP12, NSP13, NSP14, ORF3, ORF6 and M protein inhibit Sendai virus-induced IFN-β promoter activation, whereas NSP2 and S protein exert opposite effects. Further analyses suggest that ORF6 inhibits both type I IFN production and downstream signalling, and that the C-terminus region of ORF6 is critical for its antagonistic effect. Finally, it was observed that IFN-β treatment effectively blocks SARS-CoV-2 replication. In summary, this study shows that SARS-CoV-2 perturbs host innate immune response via both its structural and non-structural proteins, and thus provides insights into the pathogenesis of SARS-CoV-2.
SARS-CoV-2 is highly pathogenic in humans and poses a great threat to public health worldwide. Clinical data shows a disturbed type I interferon (IFN) response during the virus infection. It has been found that the nucleocapsid (N) protein of SARS-CoV-2 plays an important role in the inhibition of interferon beta (IFN-β) production. N-protein also suppresses IFN-β production, induced by the retinoic acid-inducible gene I (RIG-I) pathway, which is the crucial pattern recognition receptor (PRR) required for identifying RNA viruses. This suggests that N-protein interacts with the RIG-I protein and suppresses the IFN-β response by blocking the very first PRR–RNA-recognition step in the innate immune pathway. This discovery provides insights into the mechanism of how SARS-CoV-2 blocks interferon production. It is possible that other SARS-CoV-2 proteins can inhibit or promote interferon production and there may be other PRRs to recognise SARS-CoV-2, but this still provides a potential line of research into new therapies for SARS-CoV-2 infection
Elderly COIVD-19 patients report varying levels of respiratory, physical and psychological dysfunction. With the experience of improved and discharged COVID-19 patients, timely respiratory rehabilitation may improve prognosis, and improve quality of life in such patients, A recent study reported the effects of 6-week respiratory rehabilitation training on respiratory function, mobility and psychological function in 72 elderly patients with COVID-19 where 36 underwent rehabilitation intervention and 36 did not. Pulmonary function tests, functional tests (6-min walk test), Quality of life (QoL) assessments, activities of daily living, and mental status tests were measured. After 6 weeks significant improvement was observed in the intervention group. This study concludes that Six-week respiratory rehabilitation can improve respiratory function, QoL and anxiety of elderly patients with COVID-19, but it has little significant improvement on depression in the elderly.
Patients with coronavirus disease 2019 (COVID-19) have elevated D-dimer levels meaning, the patients blood shows signs of clotting, coagulation and embolism. Such thrombotic complications were studied further in 400 patients (144 critically ill) who were receiving standard anticoagulants. Coagulation and inflammatory parameters were compared and logistic models applied to assess the utility of these markers in predicting coagulation-associated complications, critical illness, and death in COVID-19 patiemts. Elevated D-dimer at initial stages was predictive of complications for thrombosis, bleeding complications, thrombotic complications, critical illness, and death. Beyond D-dimer, thrombosis was primarily associated with inflammatory markers rather than coagulation parameters. Randomised clinical trials are necessary to determine the optimal dose and course of treatment in such patients who also have COVID-19.