Structure-based drug discovery against M. tuberculosis MptpB: a novel strategy

结核病是影响人类的最古老和最持久的细菌传染病之一。尽管随着疫苗和抗生素的引入，在控制结核病传播方面取得了重大进展，但仍有三分之一的人口受到感染。该疾病最近死灰复燃，加上耐药性的发展，有可能扩大成为未来的流行病。因此，迫切需要新的治疗方法来对抗病原体。药物开发的一个主要瓶颈是资源和专门知识一般都集中在私营部门。此外，企业非常不愿意在穷人的疾病上投入大量资金，因为这肯定会损害它们的回报效益。我们已经描述了一种已知的蛋白质的活性谱，该蛋白质是引起结核病的细菌的毒力因子，我们建议开发一种新的候选药物来治疗结核病。我们已经发现了一些化合物，它们是这种蛋白质的有效抑制剂。为了进一步实现我们的目标，我们现在必须开发我们已经确定的一些线索，并能够在体内小鼠模型中进行测试。在这个阶段，这只能在一个非营利性的学术环境中实现。为此，我们将通过x射线晶体学和计算机模拟分析抑制剂和底物与靶蛋白的分子相互作用。从结构分析中获得的信息将用于设计和合成具有更特异性和选择性的新化合物。然后，这些新化合物将被测试对蛋白质的活性，并在细胞分析和小鼠模型中进行测试，以选择最佳的候选药物用于未来的临床试验。

Tuberculosis is one of the oldest and most persistent bacterial infectious diseases that affect humans. Despite significant advances to control the spread of tuberculosis with the introduction of vaccines and antibiotics, one third of the human population is still infected. The recent resurgence of the disease, together with the development of drug resistance, is threatening to expand into a future epidemic. New therapeutic approaches are then urgently needed to fight the pathogens. A main bottleneck in the development of drugs is that generally resources and expertise are concentrated in the private sector. In addition companies are highly reluctant to allocate serious investments in poor people s diseases that would certainly compromise their return benefits. We have characterised the activity profile of a protein known to be a virulence factor for tuberculosis causing bacteria and we propose to develop a new drug candidate against this target to treat tuberculosis. We have already identified compounds, which are potent inhibitors of this protein. To take our ambitions further, we must now develop some of the leads we have identified and be able to test them with in vivo mouse models. This will only be possible in a non-profit academic environment at this stage. To do that, we will analyse the molecular interactions of the inhibitors and substrates with the target protein by X-ray crystallography and computer simulations. The information obtained from the structural analysis will be used to design and synthesise new compounds with more specific and selective properties. These new compounds will then be tested for activity against the protein and in cell assays and mouse models to select the best drug candidate for future clinical trials.