PMC:7890668 / 3812-7583
Annnotations
{"target":"http://pubannotation.org/docs/sourcedb/PMC/sourceid/7890668","sourcedb":"PMC","sourceid":"7890668","source_url":"https://www.ncbi.nlm.nih.gov/pmc/7890668","text":"3 Case study\nWe illustrate the utility of COVID-KOP by examining the linagliptin—COVID-19 connection (Fig. 1). Linagliptin is a type 2 diabetes (T2D) drug that is undergoing clinical trials for COVID-19 (https://clinicaltrials.gov/ct2/show/NCT04341935). Linagliptin inhibits dipeptidyl peptidase-4 (DPP-4), which degrades hormones stimulating insulin production (Scott, 2011). It is known to be overexpressed in patients with T2D (Barchetta et al., 2020). COVID-19 patients with T2D have a higher risk of developing more severe symptoms, possibly due to an increased expression of the host receptor ACE2 (Fang et al., 2020).\nFig. 1. Execution of a COVID-KOP query for linagliptin-COVID-19 pair. (A) Query graph; (B) answer graph for linagliptin-DPP4-T2D-COVID-19 pathway; (C) answer graph for linagliptin-ACE2-T2D-COVID-19 pathway We applied COVID-KOP to identify possible mechanistic connections between linagliptin and COVID-19 that would support its expected therapeutic effect or identify possible side effects. Using the COVID-KOP user interface, a query is constructed as follows. Individual nodes are placed and linked to specific biomedical objects (such as node n2 being a gene in Fig. 1A). The user can then link these nodes together in any order. In this case study, node n0 is matched to COVID-19; n1 is marked as any phenotypic feature linked to COVID-19; and n2 is any gene related to a phenotypic feature connected to COVID-19. Finally, n2 must also have a connection to the linagliptin.\nExecuting this query generated 47 subgraphs ranked by an algorithm implemented in ROBOKOP (Morton et al., 2019), with the pathway serving as a rationale for the linagliptin clinical trial against COVID-19 (Linagliptin-T2D-DPP4-COVID-19; Fig. 1B) ranked the highest. Three conditions—pneumonia, T2D and hypertensive disorder—were identified as associated with COVID-19. Genes associated with these conditions and also linked to linagliptin are annotated in Figure 1B. Pneumonia was not directly related to any of these genes except for transforming growth factor beta (TGFβ-1), the inhibition of which results in increased susceptibility to pneumonia in mice with a pneumonia-resistant phenotype (Neill et al., 2012). Relatedly, linagliptin has been reported to ‘significantly decrease’ TGFβ-1 transcript levels (Wang et al., 2015). Our answer graph suggests that linagliptin may inhibit TGFβ-1 transcription and thus possibly increase patients’ risk of developing more severe pneumonia, even though it may alleviate some of the more severe pathologies of COVID-19 seen in T2D patients via DPP-4 inhibition.\nWe also uncovered an additional inference associating linagliptin and Angiotensin-Converting Enzyme II (ACE2), the host receptor for SARS-CoV-2 entry: Linagliptin-ACE2-T2D-COVID-19 (Fig. 1C). Downregulation of ACE2 expression in lung tissue has been associated with severe COVID-19 clinical outcomes (Nakhleh and Shehadeh, 2020). Expression of ACE2 is increased in patients with T2D; thus, ACE inhibitors and angiotensin-receptor blockers are commonly used to treat individuals with this condition (Pal and Bhansali, 2020). A recent study (Zhang et al., 2015) demonstrated that administration of linagliptin significantly upregulated ACE2 expression and was useful in preventing angiotensin II-induced cardiac fibrosis in animal models. It is yet unclear if upregulating ACE2 would be beneficial or detrimental to patients, especially those with T2D; nevertheless, this inference reveals an additional pathway linking linagliptin and COVID-19. Thus, COVID-KOP could help recovering known biochemical pathways associating a drug with COVID-19 (linagliptin-DPP4-T2D -COVID-19) as well as offer potentially novel inferences (linagliptin-TGFB1-Pneumonia-COVID-19).","divisions":[{"label":"title","span":{"begin":0,"end":12}},{"label":"p","span":{"begin":13,"end":624}},{"label":"figure","span":{"begin":625,"end":831}},{"label":"label","span":{"begin":625,"end":632}},{"label":"caption","span":{"begin":634,"end":831}},{"label":"p","span":{"begin":634,"end":831}},{"label":"p","span":{"begin":832,"end":1503}},{"label":"p","span":{"begin":1504,"end":2610}}],"tracks":[]}