Structure-based design of pan-coronavirus inhibitors targeting host cathepsin L and calpain-1.

Respiratory disease caused by coronavirus infection remains a global health crisis. Although several SARS-CoV-2-specific vaccines and direct-acting antivirals are available, their efficacy on emerging coronaviruses in the future, including SARS-CoV-2 variants, might be compromised. Host-targeting antivirals provide preventive and therapeutic strategies to overcome resistance and manage future outbreak of emerging coronaviruses.

Macrocyclization of Maleimide-Decorated Peptides via Late-Stage Rh(III)-Catalyzed Trp(C7) Alkenylation.

Here, we report a novel strategy for constructing maleimide-containing peptides and cyclic peptides using Rh(III)-catalyzed tryptophan (Trp) (C7) alkenylation, which is challenging due to the inherent reactivity of the indole benzenoid ring. This method is scalable and exhibits broad substrate scope. The utility of this protocol could further be demonstrated by the synthesis of peptide conjugates with natural products and amino acids as well as the construction of maleimide-braced cyclic peptides.

Novel Sphingosine Kinase 1 Inhibitor Suppresses Growth of Solid Tumor and Inhibits the Lung Metastasis of Triple-Negative Breast Cancer.

Targeting sphingosine kinase 1 (SphK1) has become a novel strategy for the treatment of inflammatory bowel disease and cancer the SphK1/S1P signaling pathway. However, exploration of SphK1 inhibitor therapeutic applications has been hampered by the poor pharmacokinetic properties of these SphK1 inhibitors. Herein, we report the structural optimization and structure-activity relationship studies of a series of novel SphK1 inhibitors.

Catalytic System-Controlled Divergent Reaction Strategies for the Construction of Diversified Spiropyrazolone Skeletons from Pyrazolidinones and Diazopyrazolones.

A catalytic system-controlled divergent reaction strategy was here reported to construct four types of intriguing spiroheterocyclic skeletons from simple and readily available starting materials via a precise chemical bond activation/[n+1] annulation cascade. The tetraazaspiroheterocyclic and trizazspiroheterocyclic scaffolds could be independently constructed by a selective N-N bond activation/[n+1] annulation cascade, a C(sp )-H activation/[4+1] annulation and a novel tandem C(sp )-H/C(sp )-H bond activation/[4+1] annulation strategy, along with a broad scope of substrates, moderate to excellent yields and valuable transformations. More importantly, in these transformations, we are the first time to capture a N-N bond activation and a C(sp )-H bond activation of pyrazolidinones under different catalytic system.

Discovery of novel ceramide analogs with favorable pharmacokinetic properties and combination with AKT inhibitor against colon cancer.

Ceramides have emerged as potential therapeutic option with novel mechanism to affect the proliferation, differentiation, senescence, and apoptosis of cancer cells through regulation of multiple signal transduction. Aiming at the improvement of the apoptosis activity and pharmacokinetic profiles of ceramides, a novel series of ceramide analogs were developed through structure simplification and conformation restriction. Among them, compound 12 bearing an alkoxyl naphthyl motif, with favorable rat pharmacokinetic properties, showed better anti-proliferative activity against various colon cancer cells (IC ∼20 μM) than other ceramide analogues, as well as the synergistic effect combined with AKT inhibitor MK2206.

Structure-based design of antiviral drug candidates targeting the SARS-CoV-2 main protease.

SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) is the etiological agent responsible for the global COVID-19 (coronavirus disease 2019) outbreak. The main protease of SARS-CoV-2, M, is a key enzyme that plays a pivotal role in mediating viral replication and transcription. We designed and synthesized two lead compounds ( and ) targeting M Both exhibited excellent inhibitory activity and potent anti-SARS-CoV-2 infection activity.