Francesconi Oscar, Donnici Lorena, Fragai Marco, Pesce Elisa, Bombaci Mauro, Fasciani Alessandra, Manganaro Lara, Conti Matteo, Grifantini Renata, De Francesco Raffaele, Nativi Cristina, Roelens Stefano
Dipartimento di Chimica, DICUS, University of Florence, Florence, Italy.
Fondazione INGM - Istituto Nazionale Genetica Molecolare "Romeo ed Enrica Invernizzi", Milan, Italy.
iScience. 2022 May 20;25(5):104239. doi: 10.1016/j.isci.2022.104239. Epub 2022 Apr 11.
Developing strategies against the SARS-CoV-2 is currently a main research subject. SARS-CoV-2 infects host cells by binding to human ACE2 receptors. Both, virus and ACE2, are highly glycosylated, and exploiting glycans of the SARS-CoV-2 envelope as binding sites for ACE2 represents a virus strategy for attacking the human host. We report here that a family of mannose-binding synthetic carbohydrate-binding agents (CBAs) inhibits SARS-CoV-2 infection, showing broad neutralizing activity several variants of the spike protein. Preliminary tests indicated that the investigated CBAs interact with the spike protein rather than with ACE2. For a lead compound (IDS060), which has been selected among others for its lack of cytotoxicity, evidence of binding to the RBD of the spike protein has been found by NMR experiments, while competitive binding assays in the presence of IDS060 showed inhibition of binding of RBD to hACE2, although neutralizing activity was also observed with variants showing reduced or depleted binding.
目前，研发针对严重急性呼吸综合征冠状病毒2（SARS-CoV-2）的策略是一个主要研究课题。SARS-CoV-2通过与人血管紧张素转换酶2（ACE2）受体结合来感染宿主细胞。病毒和ACE2都高度糖基化，利用SARS-CoV-2包膜聚糖作为ACE2的结合位点是病毒攻击人类宿主的一种策略。我们在此报告，一类甘露糖结合合成碳水化合物结合剂（CBA）可抑制SARS-CoV-2感染，对刺突蛋白的多个变体显示出广泛的中和活性。初步测试表明，所研究的CBA与刺突蛋白相互作用，而非与ACE2相互作用。对于一种因其无细胞毒性而被选中的先导化合物（IDS060），通过核磁共振实验发现了其与刺突蛋白受体结合域（RBD）结合的证据，而在IDS060存在下的竞争性结合试验显示，RBD与人类ACE2（hACE2）的结合受到抑制，尽管对于结合减少或耗尽的变体也观察到了中和活性。
