USP2 inhibition prevents infection with ACE2-dependent coronaviruses in vitro and is protective against SARS-CoV-2 in mice.

Targeting angiotensin-converting enzyme 2 (ACE2) represents a promising and effective approach to combat not only the COVID-19 pandemic but also potential future pandemics arising from coronaviruses that depend on ACE2 for infection. Here, we report ubiquitin specific peptidase 2 (USP2) as a host-directed antiviral target; we further describe the development of MS102, an orally available USP2 inhibitor with viable antiviral activity against ACE2-dependent coronaviruses. Mechanistically, USP2 serves as a physiological deubiquitinase of ACE2, and targeted inhibition with specific small-molecule inhibitor ML364 leads to a marked and reversible reduction in ACE2 protein abundance, thereby blocking various ACE2-dependent coronaviruses tested. Using human ACE2 transgenic mouse models, we further demonstrate that ML364 efficiently controls disease caused by infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), as evidenced by reduced viral loads and ameliorated lung inflammation. Furthermore, we improved the in vivo performance of ML364 in terms of both pharmacokinetics and antiviral activity. The resulting lead compound, MS102, holds promise as an oral therapeutic option for treating infections with coronaviruses that are reliant on ACE2.

De Novo Design of κ-Opioid Receptor Antagonists Using a Generative Deep-Learning Framework.

Likely effective pharmacological interventions for the treatment of opioid addiction include attempts to attenuate brain reward deficits during periods of abstinence. Pharmacological blockade of the κ-opioid receptor (KOR) has been shown to abolish brain reward deficits in rodents during withdrawal, as well as to reduce the escalation of opioid use in rats with extended access to opioids. Although KOR antagonists represent promising candidates for the treatment of opioid addiction, very few potent selective KOR antagonists are known to date and most of them exhibit significant safety concerns. Here, we used a generative deep-learning framework for the de novo design of chemotypes with putative KOR antagonistic activity. Molecules generated by models trained with this framework were prioritized for chemical synthesis based on their predicted optimal interactions with the receptor. Our models and proposed training protocol were experimentally validated by binding and functional assays.

Targeted Degradation of PRC1 Components, BMI1 and RING1B, via a Novel Protein Complex Degrader Strategy.

Polycomb repressive complex 1 (PRC1) is an essential epigenetic regulator that mainly controls histone H2A Lys119 mono-ubiquitination (H2AK119ub). B cell-specific Moloney murine leukemia virus Integration site 1 (BMI1) and really interesting new gene 1B (RING1B) are PRC1 core components and play critical roles in the development of various cancers. However, therapeutic agents targeting PRC1 are very limited. In this study, MS147, the first degrader of PRC1 core components, BMI1 and RING1B, is discovered via a novel protein complex degradation strategy that utilizes the target protein's interacting partner protein (embryonic ectoderm development (EED)). MS147, which comprises an EED small-molecule binder linked to a ligand of the E3 ligase von Hippel-Lindau (VHL), degrades BMI1/RING1B in an EED-, VHL-, ubiquitination-, and time-dependent manner. MS147 preferentially degrades BMI1/RING1B over polycomb repressive complex 2 (PRC2) core components. Consequently, MS147 effectively reduces H2AK119ub, but not histone H3 Lys27 tri-methylation (H3K27me3), which is catalyzed by PRC2. Furthermore, MS147 effectively inhibits the proliferation of cancer cell lines that are insensitive to PRC2 inhibitors/degraders. Overall, this study provides a novel BMI1/RING1B degrader, which is a useful chemical tool to further investigate the roles of PRC1 in cancer, and a novel protein complex degradation strategy, which can potentially expand the degradable human proteome.