Small Molecule Anti-Viral Therapeutics for SARS-CoV-2

Agastiya Biotech has discovered its previously tested anti-cancer small molecule AB001 as a viable SARS-CoV-2 virus therapeutic. Based on in silico models, AB001 acts on ACE-2 to inhibit the entry of the virus into the cell and also works on NSP15 to prevent its replication, demonstrating minimal to no toxicity.  Thus, AB001 has promise to become a breakthrough small molecule for both cancer and viral therapeutics.  Originally the study was carried out for cancer therapeutics in vitro and in vivo and is currently in testing for Covid-19 treatment.

Currently multiple direct-acting antivirals are under evaluation in randomized control trials to treat COVID-19 including hydroxychloroquine, remdesivir, lopinavir/ritonavir.  AB001 exerts its orally bioavailable, broad-spectrum antiviral effect through multiple mechanisms including blocking viral entry and targeting a host factor required for replication.  

Stopping SARS-CoV-2 Entry and Replication

AB001 inhibits ACE-2 and NSP-15 which are responsible for entry and replication of viruses in human cells in silico.  Prior in vivo studies show the molecule has the ability to activate CD4+ helper T cells and CD8+ cytotoxic T cells and generates an immune response in the body to protect against viral infections.

     Figure: Steps in Coronavirus Replication that AB001 Small Molecule Targets

Mechanism of Action in the Lungs 

In the animal model AB001 decreased production of cytokines (tumor necrosis factor alpha [TNF-α] and interleukin-6 [IL-6]) and chemokines (CXCL10, CCL2, CCL3, CCL5), and were correlated with migration of Natural Killer cells and macrophages and observed in the lungs.

By day 7 of treatment, histopathological evidence shows normal lung pathology without any pneumonitis observed and a decreased expression of cytokines (TNF-α, IL-6, gamma interferon [IFN-γ], IL-2, and IL-5), chemokines (CXCL9, CXCL10, CCL2, CCL3, and CCL5), and receptors (CXCR3, CCR2, and CCR5), was detected in the lungs, associated with an influx of T lymphocytes. There were no signs of clinical illness and histopathological evidence of disease characterized by bronchiolitis, interstitial pneumonitis, diffuse alveolar damage and fibrotic scarring.

Targeting Cytokine Storms in the Lungs

AB001 may control cytokine storms by decreasing the inflammation in the lungs. The hypothesis is attributed to the intelligent, discriminatory behavior of AB001 in its various responses to cancer cells, primarily its ability to exclude the normal cells in the apoptosis process. AB001 is very adaptive to occasions and needs.

AB001 molecules have a significant effect on targeting specific lung cancer stem cells and induces apoptosis and inhibits metastasis without harming the normal cells which aids in the treatment of cancer therapy. Orally bioavailable, multi-tyrosine-kinase inhibitor with 120 target proteins, induces apoptosis and suppresses the invasiveness of Lung Cancer Stem Cells with no toxicity to normal cells. There were no signs of discomfort, cardiovascular or respiratory disorders observed in animals after the administration throughout the study.

Signaling Pathways

AB001 inhibits WNT signaling by reducing LRP6 phosphorylation and WNT target gene expression both in vivo and in vitro, capable of reducing self-renewal and stemness of CSCs.

It inhibits cell proliferation, Epithelial Mesenchymal Transition, stemness, invasion and migration via specifically targeting canonical TGFβ/BMP-SMADs pathways and Wnt/Hedgehog pathway.

Toxicity

AB001, as proved both in vitro and in vivo, has minimum or negligible toxicity in relation to heart, lung, kidney and the brain.

Enhancing Immune System Response

Previous study has shown that pulmonary migration of NK cells and macrophases plays a significant role in the clearance of SARS-CoV.  The innate response itself, without the assistance from the CD8+ T cells and antibodies, is able to control SARS-CoV-2 infection by increasing the production of cytokines and chemokines. Whether the addition of NK cells could help to reach viral clearance in COVID-19 pneumonia is under phase I trial (NCT04280224) in China estimated to be completed by the end of 2020. Several companies aim to repurpose their anti-cancer NK-based products to treat COVID-19. Data from our research shows treatment with AB001 in animal tumor model increases the number and activity of cytotoxic T cells and promoted the activation of macrophages NK cell and DC which facilitate Antigen Presenting Cells(APC) to CD4+ and CD8+ through capture, internalization, processing and presentation of antigens via MHC class I and II molecules.

The studies carry evidence that AB001 may protect SARS-CoV-2 infected patients from progression to severe disease and prophylactically protect health care workers in areas with existing pandemic SARS-CoV-2. We suggest that AB001 should be assessed in human patients suffering from the novel coronavirus disease. Repetition of research in vitro is needed to confirm the findings in the future.

Please contact media@agastiyabiotech.com for more details or a copy of our research publication.