New Strategies for Responding to SARS-CoV-2: The Present and Future of Dual-Target Drugs

Abstract

The 2019 coronavirus disease (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has resulted in millions of deaths, posing a serious threat to public health and safety. Rapid mutations of SARS-CoV-2 and complex interactions among multiple targets during infection pose a risk of expiry for small molecule inhibitors. This suggests that the traditional concept of "one bug, one drug" could be ineffective in dealing with the coronavirus. The dual-target drug strategy is expected to be the key to ending coronavirus infections. However, the lack of design method and improper combination of dual-targets poses obstacle to the discovery of new dual-target drugs. In this Perspective, we summarized the profiles concerning drug design methods, structure−activity relationships, and pharmacological parameters of dual-target drugs for the treatment of COVID-19. Importantly, we underscored how target combination and rational drug design illuminate the development of dualtarget drugs for SARS-CoV-2. ■ SIGNIFICANCE• This is the first Perspective on dual-target drugs for treating coronavirus. • Dual-target drugs, acting on multiple pathways, offer enhanced efficacy and can delay resistance compared to single-target treatments. • Drug repurposing for dual-target design can significantly shorten the timeline for clinical trials, addressing urgent medication needs during the early COVID-19 outbreak. • The introduction of covalent warheads can compensate for active site similarity issues, aiding in the development of high-affinity dual-target inhibitors.