PMC:7796052 / 941-6254 JSONTXT

{"target":"https://pubannotation.org/docs/sourcedb/PMC/sourceid/7796052","sourcedb":"PMC","sourceid":"7796052","source_url":"https://www.ncbi.nlm.nih.gov/pmc/7796052","text":"1. Introduction\nAbout 20% of patients infected with SARS-Cov-2 develop respiratory complications, including pneumonia, that may evolve to severe hypoxemia, acute respiratory distress syndrome (ARDS), pulmonary edema, shock, metabolic acidosis, coagulation dysfunction and multiple organ functional failure [1,2]. Covid-19 patients with severe symptoms exhibit an immune response characterized by elevated serum levels of diverse proinflammatory molecules, including interleukin-6 (IL-6) [3,4,5,6]. Presently, these patients are treated with anti-inflammatory drugs like dexamethasone [7] or cytokine inhibitors, combined with antibiotics to treat secondary infections, sometimes combined with remdesivir, an antiviral originally developed to treat hepatitis C and tested against the Ebola virus disease to reduce the viral load [8].\nTreatment of Covid-19 urges a deeper understanding of the underlying molecular mechanisms involved in disease progression to provide a prompt therapeutical response with an adequate use of available drugs, including drug repurposing. Indeed, there is a number of ongoing clinical trials to test the efficacy of diverse FDA-approved drugs against Covid-19. Among them, a few involve assessment of the therapeutic efficacy of IL-6 inhibition, unfortunately without reporting conclusive results [9,10,11]. Recently, it was proposed that dysregulated bradykinin (BK) signaling could be the trigger of the cytokine storm observed in patients with severe Covid-19 [12,13,14,15]. The rational for this hypothesis relies on the increased availability of BK and its metabolite des-Arg9-BK in Covid-19 patients, due to the downregulation of angiotensin converting enzyme 2 (ACE2), the entry protein of SARS-Cov-2 [16]. Indeed, ACE2 downregulation increases the amount of angiotensin I processed by the angiotensin-converting enzyme (ACE) with a concomitant decrease of its degradation activity on BK. Moreover, levels of des-Arg9-BK are also increased due to the diminished degradative activity of ACE2 caused by its downregulation [12]. The BK hypothesis is consistent with the observed elevated levels of IL-6 in Covid-19 patients [17]. This new perspective suggests that inhibition of BK signaling may be a suitable therapy to avoid the cytokine storm and its consequences. Indeed, as a proof of principle, preliminary results from a limited study suggests that inhibition of the BK signaling is associated with a decrease of the oxygen supplementation needed by Covid-19 patients [18].\nNowadays, icatibant is the only BK antagonist approved as therapeutic agent for the treatment of hereditary angioedema [19], in spite of the number of selective BK ligands described in the literature [20]. The discovery of the bradykinin hypothesis prompted the launch of an ongoing clinical trial to assess the benefits of icatibant for the treatment of covid-19 patients [21]. In other to swiftly test the efficacy of alternative BK antagonists with diverse pharmacological profiles for the treatment of Covid-19, drug repurposing represents a valuable strategy [22]. To this aim, we recently carried out a virtual screening study on the DrugBank database [23] aimed at identifying BK ligands among drugs already approved by the FDA [24]. The study was carried out using four points common to the pharmacophores derived for the B1 and B2 bradykinin receptors recently reported that were used as queries for the search [25,26,27]. Hits identified were subsequently subjected to a docking study using the Molecular Operating Environment (MOE) program [28].\nThe virtual screening process permitted the identification of a small set of drugs as prospective nonselective BK ligands, as described elsewhere [24]. Specifically, the DrugBank database, containing a total of 1703 molecules, was screened for compounds that fulfilled a common pharmacophore for the B1 and B2 receptors. The study identified eight drugs including raloxifene, sildenafil, cefepime, cefpirome, imatinib, ponatinib, abemaciclib and entrectinib. Subsequently, the eight compounds were purchased and tested for their capacity to displace a reference ligand in any of the two bradykinin receptors B1 and B2, respectively at 20 µM. Three of the compounds including raloxifene, sildenafil and cefepime displaced the reference ligand from B2, which represents a 40% success rate as found in similar studies [29]. However, none of the compounds exhibited affinity for the B1 receptor at this concentration. This might be due to the steric hindrance that was not properly included in the virtual screening search. Raloxifene, the most potent antagonist identified was further investigated in a functional study in vitro, exhibiting an IC50 of ~16 µM. Moreover, the compound showed a weak partial agonist profile with a maximal activity of ~20%. Ralixofene is a selective estrogen receptor modulator, exerting estrogen agonist action in some target tissues while acting as an estrogen antagonist in others [30]. The compound was approved a few years ago for the treatment of osteoporosis in postmenopausal women, as well as for cancer chemoprotection. The discovery of a new pharmacodynamic profile of relixofene as a BK partial agonist opens an opportunity for its repurposing as a therapeutic agent for the treatment of severe Covid-19.","divisions":[{"label":"title","span":{"begin":0,"end":15}},{"label":"p","span":{"begin":16,"end":832}},{"label":"p","span":{"begin":833,"end":2512}},{"label":"p","span":{"begin":2513,"end":3569}}],"tracks":[{"project":"LitCovid-PubTator","denotations":[{"id":"45","span":{"begin":466,"end":479},"obj":"Gene"},{"id":"46","span":{"begin":481,"end":485},"obj":"Gene"},{"id":"47","span":{"begin":29,"end":37},"obj":"Species"},{"id":"48","span":{"begin":52,"end":62},"obj":"Species"},{"id":"49","span":{"begin":322,"end":330},"obj":"Species"},{"id":"50","span":{"begin":515,"end":523},"obj":"Species"},{"id":"51","span":{"begin":783,"end":794},"obj":"Species"},{"id":"52","span":{"begin":570,"end":583},"obj":"Chemical"},{"id":"53","span":{"begin":693,"end":703},"obj":"Chemical"},{"id":"54","span":{"begin":38,"end":46},"obj":"Disease"},{"id":"55","span":{"begin":108,"end":117},"obj":"Disease"},{"id":"56","span":{"begin":145,"end":154},"obj":"Disease"},{"id":"57","span":{"begin":156,"end":191},"obj":"Disease"},{"id":"58","span":{"begin":193,"end":197},"obj":"Disease"},{"id":"59","span":{"begin":200,"end":215},"obj":"Disease"},{"id":"60","span":{"begin":217,"end":222},"obj":"Disease"},{"id":"61","span":{"begin":224,"end":242},"obj":"Disease"},{"id":"62","span":{"begin":244,"end":267},"obj":"Disease"},{"id":"63","span":{"begin":272,"end":305},"obj":"Disease"},{"id":"64","span":{"begin":313,"end":321},"obj":"Disease"},{"id":"65","span":{"begin":657,"end":667},"obj":"Disease"},{"id":"94","span":{"begin":1257,"end":1261},"obj":"Gene"},{"id":"95","span":{"begin":1380,"end":1390},"obj":"Gene"},{"id":"96","span":{"begin":1392,"end":1394},"obj":"Gene"},{"id":"97","span":{"begin":1664,"end":1695},"obj":"Gene"},{"id":"98","span":{"begin":1697,"end":1701},"obj":"Gene"},{"id":"99","span":{"begin":1750,"end":1754},"obj":"Gene"},{"id":"100","span":{"begin":1794,"end":1807},"obj":"Gene"},{"id":"101","span":{"begin":1825,"end":1854},"obj":"Gene"},{"id":"102","span":{"begin":1856,"end":1859},"obj":"Gene"},{"id":"103","span":{"begin":2021,"end":2025},"obj":"Gene"},{"id":"104","span":{"begin":2130,"end":2134},"obj":"Gene"},{"id":"105","span":{"begin":2211,"end":2213},"obj":"Gene"},{"id":"106","span":{"begin":2406,"end":2408},"obj":"Gene"},{"id":"107","span":{"begin":1579,"end":1581},"obj":"Gene"},{"id":"108","span":{"begin":2065,"end":2067},"obj":"Gene"},{"id":"109","span":{"begin":1610,"end":1612},"obj":"Gene"},{"id":"110","span":{"begin":1461,"end":1469},"obj":"Species"},{"id":"111","span":{"begin":1625,"end":1633},"obj":"Species"},{"id":"112","span":{"begin":1725,"end":1735},"obj":"Species"},{"id":"113","span":{"begin":2147,"end":2155},"obj":"Species"},{"id":"114","span":{"begin":2498,"end":2506},"obj":"Species"},{"id":"115","span":{"begin":2456,"end":2462},"obj":"Chemical"},{"id":"116","span":{"begin":846,"end":854},"obj":"Disease"},{"id":"117","span":{"begin":1179,"end":1187},"obj":"Disease"},{"id":"118","span":{"begin":1482,"end":1490},"obj":"Disease"},{"id":"119","span":{"begin":1616,"end":1624},"obj":"Disease"},{"id":"120","span":{"begin":2138,"end":2146},"obj":"Disease"},{"id":"121","span":{"begin":2489,"end":2497},"obj":"Disease"},{"id":"131","span":{"begin":2740,"end":2750},"obj":"Gene"},{"id":"132","span":{"begin":2945,"end":2947},"obj":"Gene"},{"id":"133","span":{"begin":3197,"end":3199},"obj":"Gene"},{"id":"134","span":{"begin":2674,"end":2676},"obj":"Gene"},{"id":"135","span":{"begin":2545,"end":2547},"obj":"Gene"},{"id":"136","span":{"begin":2877,"end":2885},"obj":"Species"},{"id":"137","span":{"begin":2610,"end":2631},"obj":"Disease"},{"id":"138","span":{"begin":2868,"end":2876},"obj":"Disease"},{"id":"139","span":{"begin":3019,"end":3027},"obj":"Disease"},{"id":"162","span":{"begin":4449,"end":4460},"obj":"Gene"},{"id":"163","span":{"begin":4847,"end":4864},"obj":"Gene"},{"id":"164","span":{"begin":5193,"end":5195},"obj":"Gene"},{"id":"165","span":{"begin":3681,"end":3683},"obj":"Gene"},{"id":"166","span":{"begin":5081,"end":5086},"obj":"Species"},{"id":"167","span":{"begin":3934,"end":3944},"obj":"Chemical"},{"id":"168","span":{"begin":3946,"end":3956},"obj":"Chemical"},{"id":"169","span":{"begin":3958,"end":3966},"obj":"Chemical"},{"id":"170","span":{"begin":3968,"end":3977},"obj":"Chemical"},{"id":"171","span":{"begin":3979,"end":3987},"obj":"Chemical"},{"id":"172","span":{"begin":3989,"end":3998},"obj":"Chemical"},{"id":"173","span":{"begin":4000,"end":4011},"obj":"Chemical"},{"id":"174","span":{"begin":4016,"end":4027},"obj":"Chemical"},{"id":"175","span":{"begin":4245,"end":4255},"obj":"Chemical"},{"id":"176","span":{"begin":4257,"end":4267},"obj":"Chemical"},{"id":"177","span":{"begin":4272,"end":4280},"obj":"Chemical"},{"id":"178","span":{"begin":4590,"end":4600},"obj":"Chemical"},{"id":"179","span":{"begin":4821,"end":4831},"obj":"Chemical"},{"id":"180","span":{"begin":5177,"end":5187},"obj":"Chemical"},{"id":"181","span":{"begin":5050,"end":5062},"obj":"Disease"},{"id":"182","span":{"begin":5103,"end":51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