Historically, most drugs target protein orthosteric sites. The gradual emergence of resistance hampers their therapeutic effectiveness, posing a challenge to drug development. Coadministration of allosteric and orthosteric drugs provides a revolutionary strategy to circumvent drug resistance, as drugs targeting the topologically distinct allosteric sites can restore or even enhance the efficacy of orthosteric drugs. Here, we comprehensively review the latest successful examples of such combination treatments against drug resistance, with a focus on their modes of action and the underlying structural mechanisms. Our work supplies an innovative insight into such promising methodology against the recalcitrant drug resistance conundrum and will be instructive for future clinical therapeutics.

中文翻译：

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结合变构和正构药物以克服耐药性。

历史上，大多数药物靶向蛋白质正构位点。耐药性的逐渐出现阻碍了它们的治疗效果，对药物开发提出了挑战。变构和正构药物的共同给药提供了一种规避耐药性的革命性策略，因为靶向拓扑不同的变构位点的药物可以恢复甚至增强正构药物的疗效。在这里，我们全面回顾了此类抗药性联合治疗的最新成功案例，重点介绍了它们的作用模式和潜在的结构机制。我们的工作为解决顽固的耐药性难题提供了对这种有前途的方法的创新见解，并将对未来的临床治疗具有指导意义。