Knowledge Graph-Based Approaches to Drug Repurposing for COVID-19.

The COVID-19 pandemic has motivated researchers all over the world in trying to find effective drugs and therapeutics for treating this disease. To save time, much effort has focused on repurposing drugs known for treating other diseases than COVID-19. To support these drug repurposing efforts, we built the CAS Biomedical Knowledge Graph and identified 1350 small molecules as potentially repurposable drugs that target host proteins and disease processes involved in COVID-19. A computer algorithm-driven drug-ranking method was developed to prioritize those identified small molecules. The top 50 molecules were analyzed according to their molecular functions and included 11 drugs in clinical trials for treating COVID-19 and new candidates that may be of interest for clinical investigation. The CAS Biomedical Knowledge Graph provides researchers an opportunity to accelerate innovation and streamline the investigative process not just for COVID-19 but also in many other diseases.

Role for radA/sms in recombination intermediate processing in Escherichia coli.

RadA/Sms is a highly conserved eubacterial protein that shares sequence similarity with both RecA strand transferase and Lon protease. We examined mutations in the radA/sms gene of Escherichia coli for effects on conjugational recombination and sensitivity to DNA-damaging agents, including UV irradiation, methyl methanesulfonate (MMS), mitomycin C, phleomycin, hydrogen peroxide, and hydroxyurea (HU). Null mutants of radA were modestly sensitive to the DNA-methylating agent MMS and to the DNA strand breakage agent phleomycin, with conjugational recombination decreased two- to threefold. We combined a radA mutation with other mutations in recombination genes, including recA, recB, recG, recJ, recQ, ruvA, and ruvC. A radA mutation was strongly synergistic with the recG Holliday junction helicase mutation, producing profound sensitivity to all DNA-damaging agents tested. Lesser synergy was noted between a mutation in radA and recJ, recQ, ruvA, ruvC, and recA for sensitivity to various genotoxins. For survival after peroxide and HU exposure, a radA mutation surprisingly suppressed the sensitivity of recA and recB mutants, suggesting that RadA may convert some forms of damage into lethal intermediates in the absence of these functions. Loss of radA enhanced the conjugational recombination deficiency conferred by mutations in Holliday junction-processing function genes, recG, ruvA, and ruvC. A radA recG ruv triple mutant had severe recombinational defects, to the low level exhibited by recA mutants. These results establish a role for RadA/Sms in recombination and recombinational repair, most likely involving the stabilization or processing of branched DNA molecules or blocked replication forks because of its genetic redundancy with RecG and RuvABC.