Multi-ancestry omic Mendelian randomization revealing putative drug targets of COVID-19 severity

Abstract

Drug target prioritization for new targets and drug repurposing of existing drugs for COVID-19 treatment are urgently needed for the current pandemic. COVID-19 drugs targeting human proteins will potentially result in less drug resistance but could also exhibit unintended effects on other complex diseases. Here we pooled 353 candidate drug targets of COVID-19 from clinical trial registries and the literature and estimated their putative causal effects in 11 SARS-CoV-2 related tissues on 622 complex human diseases. By constructing a disease atlas of drug targets for COVID-19, we prioritise 726 target-disease associations with evidence of causality using robust Mendelian randomization (MR) and colocalization evidence (http://epigraphdb.org/covid-19/ctda/). Triangulating these MR findings with historic drug trial information and the druggable genome, we ranked and prioritised three genes DHODH, ITGB5 and JAK2 targeted by three marketed drugs (Leflunomide, Cilengitide and Baricitinib) which may have repurposing potential with careful risk assessment.

Quantitative Structure–Activity Relationship Machine Learning Models and their Applications for Identifying Viral 3CLpro- and RdRp-Targeting Compounds as Potential Therapeutics for COVID-19 and Related Viral Infections

“… 58 In a recent multiomics study, dihydroorotate dehydrogenase was identified as a possible target for SARS-CoV-2 infection. 59 In addition, leflunomide has been shown to inhibit SARS-CoV-2 activity. 60 Diltiazem hydrochloride is a calcium channel blocker that helps to increase blood flow and variably decrease the heart rate via strong depression of the A-V node.…”

The COVID-19 Pandemic from a Human Genetic Perspective

“… 37 , 38 Thus, comprehensive assessment of the causal effects of COVID-19 drug targets on disease phenotypes will provide key information regarding their safety issue ( Figure 3 ). 39 …”

The DHODH inhibitor PTC299 arrests SARS-CoV-2 replication and suppresses induction of inflammatory cytokines

“…The de novo pyrimidine biosynthesis pathway is also critical for the excessive production of a subset of inflammatory cytokines (including interferon-gamma, monocyte chemoattractant protein-1 [MCP-1], IL-5, and IL-6) in both cultured cells and animal models of viral infection (Cheung et al, 2017;Xiong et al, 2020a). Consistent with DHODH being mechanistically central to the progression of COVID-19, a recent multi-omics study of drug targets for viral infections prioritized DHODH inhibition as one of the top three mechanisms to consider for SARS-CoV-2 treatment (Zheng et al, 2020).…”