Discovery of 3-phenyl-1,2,4-oxadiazole derivatives as a new class of SARS-CoV-2 main protease inhibitors.

The ongoing COVID-19 pandemic has led to massive infections and deaths and caused tremendous grief among the people. Although vaccines have played an important role in fighting COVID-19, the situation that the protective effect of current vaccines significantly decreases against mutated strains reminds us of the pressing need for developing effective antiviral therapeutics. The main protease (Mpro) is a key enzyme for SARS-CoV-2 viral replication and transcription and an attractive target for drug development. In this research, we report a new series of Mpro inhibitors containing 3-phenyl-1,2,4-oxadiazole. Structure-activity relationship (SAR) studies led to the discovery of the most active compound, 16d, which showed an IC50 value of 5.27 ± 0.26 µM. Collectively, we obtained a new small molecular inhibitor targeting SARS-CoV-2 Mpro, which contains a new scaffold. This compound could be taken as a lead compound for subsequent drug discovery against SARS-CoV-2.

Tailored Extracellular Vesicles: Novel Tool for Tissue Regeneration.

Extracellular vesicles (EVs) play an essential part in multiple pathophysiological processes including tissue injury and regeneration because of their inherent characteristics of small size, low immunogenicity and toxicity, and capability of carrying a variety of bioactive molecules and mediating intercellular communication. Nevertheless, accumulating studies have shown that the application of EVs faces many challenges such as insufficient therapeutic efficacy, a lack of targeting capability, low yield, and rapid clearance from the body. It is known that EVs can be engineered, modified, and designed to encapsulate therapeutic cargos like proteins, peptides, nucleic acids, and drugs to improve their therapeutic efficacy. Targeted peptides, antibodies, aptamers, magnetic nanoparticles, and proteins are introduced to modify various cell-derived EVs for increasing targeting ability. In addition, extracellular vesicle mimetics (EMs) and self-assembly EV-mimicking nanocomplex are applied to improve production and simplify EV purification process. The combination of EVs with biomaterials like hydrogel, and scaffolds dressing endows EVs with long-term therapeutic efficacy and synergistically enhanced regenerative outcome. Thus, we will summarize recent developments of EV modification strategies for more extraordinary regenerative effect in various tissue injury repair. Subsequently, opportunities and challenges of promoting the clinical application of engineered EVs will be discussed.

SARS-CoV-2 Mpro inhibitors with antiviral activity in a transgenic mouse model.

The COVID-19 pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continually poses serious threats to global public health. The main protease (Mpro) of SARS-CoV-2 plays a central role in viral replication. We designed and synthesized 32 new bicycloproline-containing Mpro inhibitors derived from either boceprevir or telaprevir, both of which are approved antivirals. All compounds inhibited SARS-CoV-2 Mpro activity in vitro, with 50% inhibitory concentration values ranging from 7.6 to 748.5 nM. The cocrystal structure of Mpro in complex with MI-23, one of the most potent compounds, revealed its interaction mode. Two compounds (MI-09 and MI-30) showed excellent antiviral activity in cell-based assays. In a transgenic mouse model of SARS-CoV-2 infection, oral or intraperitoneal treatment with MI-09 or MI-30 significantly reduced lung viral loads and lung lesions. Both also displayed good pharmacokinetic properties and safety in rats.