Rasaeifar Bahareh, Gomez-Gutierrez Patricia, Perez Juan J
Department of Chemical Engineering, Universitat Politecnica de Catalunya. ETSEIB. Av. Diagonal, 647, 08028 Barcelona, Spain.
Pharmaceuticals (Basel). 2020 Sep 21;13(9):259. doi: 10.3390/ph13090259.
Angiotensin converting enzyme 2 (ACE2) downregulation is a key negative factor for the severity of lung edema and acute lung failure observed in patients infected with SARS-CoV-2. ACE2 downregulation affects the levels of diverse peptide mediators of the renin-agiotensin-aldestosterone and kallikrein-kinin systems, compromising vascular hemostasis. Increasing evidence suggests that the inflammatory response observed in covid-19 patients is initiated by the action of kinins on the bradykinin receptors. Accordingly, the use of bradykinin antagonists should be considered as a strategy for therapeutic intervention against covid-19 illness progression. Presently, icatibant is the only bradykinin antagonist drug approved. In the present report, we investigated the molecular features characterizing non-selective antagonists targeting the bradykinin receptors and carried out a in silico screening of approved drugs, aimed at the identification of compounds with a non-selective bradykinin antagonist profile that can be evaluated for drug repurposing. The study permitted to identify eight compounds as prospective non-selective antagonists of the bradykinin receptors, including raloxifene; sildenafil; cefepime; cefpirome; imatinib; ponatinib; abemaciclib and entrectinib.
血管紧张素转换酶2（ACE2）下调是感染SARS-CoV-2的患者出现肺水肿和急性肺衰竭严重程度的关键负面因素。ACE2下调会影响肾素-血管紧张素-醛固酮系统和激肽释放酶-激肽系统中多种肽介质的水平，损害血管止血功能。越来越多的证据表明，新冠患者中观察到的炎症反应是由激肽作用于缓激肽受体引发的。因此，应考虑使用缓激肽拮抗剂作为对抗新冠疾病进展的治疗干预策略。目前，艾替班特是唯一获批的缓激肽拮抗剂药物。在本报告中，我们研究了靶向缓激肽受体的非选择性拮抗剂的分子特征，并对获批药物进行了计算机模拟筛选，旨在鉴定具有非选择性缓激肽拮抗剂特征的化合物，以便评估其药物再利用价值。该研究确定了八种化合物作为缓激肽受体的潜在非选择性拮抗剂，包括雷洛昔芬；西地那非；头孢吡肟；头孢匹罗；伊马替尼；波纳替尼；阿贝西利和恩曲替尼。
