The COVID-19 RNA-synthesizing machine: Many in the scientific community have mobilized to understand the virus that is causing the global coronavirus disease 2019 (COVID-19) pandemic. Gao et al. focused on a complex that plays a key role in the replication and transcription cycle of the virus. They used cryo–electron microscopy to determine a 2.9-angstrom-resolution structure of the RNA-dependent RNA polymerase nsp12, which catalyzes the synthesis of viral RNA, in complex with two cofactors, nsp7 and nsp8. nsp12 is a target for nucleotide analog antiviral inhibitors such as remdesivir, and the structure may provide a basis for designing new antiviral therapeutics. Science , this issue p. 779

Promising antiviral protease inhibitors: With no vaccine or proven effective drug against the virus that causes coronavirus disease 2019 (COVID-19), scientists are racing to find clinical antiviral treatments. A promising drug target is the viral main protease M ^pro , which plays a key role in viral replication and transcription. Dai et al. designed two inhibitors, 11a and 11b, based on analyzing the structure of the M ^pro active site. Both strongly inhibited the activity of M ^pro and showed good antiviral activity in cell culture. Compound 11a had better pharmacokinetic properties and low toxicity when tested in mice and dogs, suggesting that this compound is a promising drug candidate. Science , this issue p. 1331

Drug inhibition of glycosyltransferases: Mycobacteria, including the species that causes tuberculosis (TB), synthesize a complex cell wall that helps to support and protect the bacterial cells. The major components of the cell wall include complex heteropolysaccharides that are synthesized in the periplasmic space. Zhang et al. determined the cryo–electron microscopy structures of two transmembrane glycosyltransferase enzyme complexes that use a lipid-anchored sugar donor to append arabinose units to the cell wall polysaccharides. They also captured the anti-TB drug ethambutol bound within these complexes and observed that it binds in a site overlapping both donor and acceptor sugars. Mapping of resistance mutants provides a structural understanding of how resistance emerges while preserving function of the enzyme and may help to guide the development of next-generation anti-TB drugs that target these enzymes. Science , this issue p. 1211

Significance: COVID-19 is a deadly rampaging infectious disease with over 480 million cases worldwide. Unfortunately, effective therapies remain very limited. Novel antiviral agents are urgently needed to combat this global healthcare crisis. Here, we elucidate the structural basis for replicase polyprotein cleavage and substrate specificity of SARS-CoV-2 main protease (M ^pro ). Through analyzing a series of high-resolution structures of SARS-CoV-2 M ^pro throughout the proteolytic process, we demonstrate the molecular mechanism of M ^pro in proteolytic processing that confers substrate specificity. Substrate selectivity is revealed using structures of the H41A mutant in complex with six individual native cleavage substrates. Our study underscores the mechanistic function of M ^pro in the viral life cycle, which provides structural insights to develop effective inhibitors against this essential target of SARS-CoV-2.