Department of Biomedical Sciences, University of Padova, Via Ugo Bassi 58/B, 35131, Padova, Italy.
Centro Interdipartimentale di Ricerca di Miologia, CIR-Myo, University of Padova, Via U. Bassi 58/B, 35131, Padova, Italy.
Arch Toxicol. 2022 Jun;96(6):1521-1539. doi: 10.1007/s00204-022-03271-9. Epub 2022 Mar 25.
Tetanus and botulinum neurotoxins cause the neuroparalytic syndromes of tetanus and botulism, respectively, by delivering inside different types of neurons, metalloproteases specifically cleaving the SNARE proteins that are essential for the release of neurotransmitters. Research on their mechanism of action is intensively carried out in order to devise improved therapies based on antibodies and chemical drugs. Recently, major results have been obtained with human monoclonal antibodies and with single chain antibodies that have allowed one to neutralize the metalloprotease activity of botulinum neurotoxin type A1 inside neurons. In addition, a method has been devised to induce a rapid molecular evolution of the metalloprotease domain of botulinum neurotoxin followed by selection driven to re-target the metalloprotease activity versus novel targets with respect to the SNARE proteins. At the same time, an intense and wide spectrum clinical research on novel therapeutics based on botulinum neurotoxins is carried out, which are also reviewed here.
破伤风毒素和肉毒神经毒素分别通过将金属蛋白酶递送至不同类型的神经元内，特异性切割 SNARE 蛋白而导致破伤风和肉毒中毒的神经麻痹综合征，SNARE 蛋白对于神经递质的释放是必需的。为了设计基于抗体和化学药物的改良疗法，正在对其作用机制进行深入研究。最近，已利用人源单克隆抗体和单链抗体取得重大成果，从而使人们能够中和神经元内的 A1 型肉毒神经毒素的金属蛋白酶活性。此外，还设计了一种方法来诱导肉毒神经毒素金属蛋白酶结构域的快速分子进化，然后进行选择，使金属蛋白酶活性针对 SNARE 蛋白的新型靶标重新靶向。与此同时，还在进行基于肉毒神经毒素的新型治疗方法的强烈和广泛的临床研究，本文也对此进行了综述。
