Overcoming Target-Dependent Resistance

Overcoming Pathway-Dependent Resistance

Concluding Remarks

References

Coadministration of Allosteric and Orthosteric Drugs: A Novel Strategy to Tackle Drug Resistance

As a detrimental problem in modern biomedicine, the inevitable emergence of drug resistance poses a great challenge to pharmaceutics and threatens global health [1–۷]. It is a sophisticated evolving process involving multiple events on the molecular pathway, and even organismal levels. Based on the underlying mechanism, drug resistance is classified as target-dependent resistance (see Glossary), caused by changes within the original targets, and pathway-dependent resistance, resulting from alterations in the relevant collateral pathways) [4,8,9]. Different methodologies are applicable for tackling different types of resistance; for example, structure-based drug design is more suitable against target-dependent resistance, whereas the multitargeted approach of polypharmacology may be a better choice against pathway-dependent resistance [10–۱۲]. Many excellent reviews have already discussed various approaches to combat resistance, but most of them only focus on either drug optimization or combined treatments with different types of therapies [5,12–۱۴]. Stemming from rapid developments in structural biology and protein allostery research [15–۲۰], allosteric drugs can resensitize resistant targets and selectively target resistance-related signaling pathways, thereby restoring the efficacy of orthosteric drugs. Moreover, compared with monotherapy, double- or even multiple-drugging strategies can cover a broader therapeutic spectrum, achieve synergistic effects, and contribute to better clinical outcomes. Thus, combination therapy with allosteric and orthosteric drugs provides an unprecedented opportunity to overcome the notorious problem of drug resistance and boost the development of next-generation pharmacological agents. With the goal of forwarding this notion, this review first outlines typical examples of combined treatments to combat clinically relevant resistance, reviewing their modes of action and future perspectives in detail. Then, it discusses the current state of this combinatorial strategy, presenting the existent obstacles as well as possible solutions. This review highlights a promising tactic for overcoming the long-standing conundrum of drug resistance and will hopefully be instructive for future drug discovery and development.