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随着多药耐药和广泛耐药结核分枝杆菌感染病例在世界范围内的日益增多,迫切需要该领域的药物研究工作者开发出具有新的作用靶点、不易导致病原菌发生耐药性变异的新型抗分枝杆菌药物。研究者们已经发现,结核分枝杆菌中的3个基因,即recA,dnaB和sutB,均受到内含肽(intein)的调控,而这些内含肽只有通过蛋白剪接(protein splicing)过程才能由本无活性的前体蛋白活化为功能性蛋白。这就提示,蛋白剪接可以作为抗结核药物的一个新的作用靶点。上述3个基因中的2个是细菌生长所必需的,而第3个基因易产生耐药突变,因此,能够废除细菌的2个独自重要的功能并同时能降低细菌变异速度的蛋白剪接抑制剂将不太可能诱导细菌产生耐药性。一种以蛋白为基础的用于蛋白剪接抑制剂筛选的高通量筛选系统已经建立起来,并用于筛选小分子化合物分子库,而且已经获得并确认了50多个对分枝杆菌IC50较低的化合物。其中,大多数已被确认的蛋白剪接抑制剂属亲电子剂,可通过与催化的半胱氨酸残基结合不可逆地抑制蛋白剪接。如果对这些抑制剂进行结构修饰,使之能嵌入RecA内含肽的已知晶体结构中,应该能够获得一类可用于治疗耐药结核病的新药。
With the increase of multi-drug resistance and extensively drug-resistant cases of Mycobacterium tuberculosis in the world, there is an urgent need for drug research workers in this field to develop new therapeutic targets that will not easily lead to resistance mutations in pathogens New anti-mycobacterial drug. Researchers have found that three genes in M. tuberculosis, recA, dnaB, and sutB, are regulated by inteins that can only be expressed by a protein splicing process Inactive precursor protein is activated as a functional protein. This suggests that protein splicing can be used as a new target of anti-TB drugs. Two of the three genes are required for bacterial growth, and the third gene is susceptible to drug-resistant mutations. Therefore, a protein splice inhibitor that abrogates two uniquely important functions of bacteria while reducing the rate of bacterial variation It will be less likely to induce bacterial resistance. A protein-based, high-throughput screening system for screening of protein splicing inhibitors has been established and used to screen small molecular compound libraries and more than 50 high-throughput screening assays have been obtained for more than 50 Compound. Among them, most of the known protein splicing inhibitors are electrophiles which can irreversibly inhibit protein splicing by binding to catalytic cysteine residues. If these inhibitors are structurally modified to incorporate the known crystal structure of the RecA inteins, a new class of drugs that can be used to treat drug-resistant TB should be available.