COVID-19 Special Project
The RIKEN Program for Drug Discovery and Medical Technology Platforms (DMP) has jumped to action in response to the global COVID-19 outbreak caused by the novel coronavirus SARS-CoV-2, launching research on therapeutic drugs and immunotherapies in collaboration with technology platform units established at RIKEN life science centers (Center for Sustainable Resource Science, Center for Biosystems Dynamics Research, Center for Integrative Medical Sciences, and Medical Sciences Innovation Hub Program), as well as external research institutions. The COVID-19 pandemic is both a global health and economic crisis, and RIKEN is committed to promoting global research and development by publishing experimental/computational results, as well as by actively promoting joint research and collaborations. Joint research is currently being conducted with The University of Tokyo, National Institute of Infectious Diseases, National Cancer Center, etc.
- March 30, 2020: RIKEN DMP launches special project to combat COVID-19
DMP is working toward the development of therapeutics against COVID-19 based on two strategies, one short- and the other mid-/long-term. The short-term strategy is to spend three years identifying existing drugs that are already on the market for other diseases that may be effective against the disease, with the goal to get them into the clinic as quickly as possible. As a mid-/long-term strategy, we are looking three to five years ahead to develop new therapeutic agents and immunotherapies with strong efficacy and safety. DMP is now gradually moving from the short-term therapeutic drug development to the mid-/long-term development strategy.
The project is looking to develop therapeutic drugs and immunotherapy targeting spike proteins and envelope proteins on the viral surface, in addition to the main protease, papain-like protease, RNA-dependent RNA polymerase and TMPRSS2 that function in viral invasion and replication processes.
Development of therapeutic drugs targeting Main protease / Papain-like protease
When viruses invade cells they produce a long protein (polyprotein) based on the genetic information in their own RNA. The polyprotein molecules are cleaved into more than a dozen fragments by the virus-derived “main protease” and “papain-like protease,” which are then used for viral proliferation and for the formation of new virus particles. By targeting this mechanism, we aim to develop drugs that inhibit the function of those proteases and suppress viral replication in cells.
Development of therapeutic drugs targeting RNA-dependent RNA polymerase (RdRp)
RNA-dependent RNA polymerase (RdRp) is an enzyme that replicates viral RNA. Avigan, an anti-influenza drug, and Lemdesivir, which has a clinical track record against Ebola hemorrhagic fever, are nucleic acid-related compounds that inhibit the function of this enzyme and suppress viral replication. We are looking for drug candidates that do not have a nucleic acid structure and have few side effects.
Development of therapeutic drugs targeting TMPRSS2
The surface of the COVID-19 virus has protrusions called “spike proteins” that bind to the ACE2 receptor on the surface of human cells, forming a precursor. The binding site of the precursor is modified by TMPRSS2, an enzyme expressed in human cells, allowing the virus to invade. Drugs that inhibit the action of TMPRSS2 could effectively block the entry of viruses into cells. Since TMPRSS2 is a human enzyme, it is expected that inhibitors will not be affected by viral mutations.
Immunotherapy using artificial adjuvant vector cells (aAVC)
aAVCs are cells loaded with glycolipids, which activate innate immunity, and antigens, which activate acquired immunity. Until now, aAVCs have been developed for cancer immunotherapy. A RIKEN team hypothesized that using aAVCs might make it possible to suppress COVID-19 with a double-pronged attack from both innate and acquired immunity. This could be done by administering aAVCs carrying spike proteins and envelope proteins on the virus surface as antigens to patients.
- July 1, 2016: New anti-cancer strategy mobilizes both innate and adaptive immune response
- September 2, 2019: RIKEN and Astellas Pharma Inc. sign exclusive worldwide license agreement (news article in Japanese)
Development of antibody drugs
RIKEN scientists are developing antibody therapies, based on the idea of targeting spike proteins and TMPRSS2. In the development of antibody drugs, our aim is to optimize the design of antibodies by making full use of RIKEN's molecular simulation and AI technologies.
Drug discovery based on structural analysis of biomolecules related to COVID-19
This project aims to clarify the quaternary structures of various proteins involved in SARS-CoV-2 infection, taking them as drug targets for COVID-19. Some of the target proteins have quaternary structures consisting of multiple proteins such as non-structural proteins (NSPs) or have large degrees of freedom. Depending on their properties, the project is using cryo-electron microscopy and nuclear magnetic resonance (NMR) to obtain structural information useful for design.
Drug discovery research based on molecular simulations of biomolecules related to COVID-19 and artificial intelligence (AI)
Many of the candidate proteins for COVID-19 drug targets have flexible protein surfaces and the dispersive force interactions are important. Preliminary studies have shown that conventional docking methods do not have sufficient ability to predict activity. This project will work to select candidate compounds by applying a new activity prediction method with higher accuracy combining FMO (quantum chemical calculation) and AI.
- March 23, 2020 RIKEN DMP releases simulation data for molecular dynamics of the main protease in the novel coronavirus (SARS-CoV-2) (press release in Japanese)
- April 17, 2020 New dataset for drug design uses quantum mechanics-based interactions of new coronavirus proteins and drug candidates
As of June 30, 2021