An orally available M/TMPRSS2 bispecific inhibitor with potent anti-coronavirus efficacy in vivo.

Coronaviruses have caused three major endemics in the past two decades. Alarmingly, recent identification of novel zoonotic coronaviruses that caused human infections suggests the risk of future coronavirus outbreak caused by spillover infection from animal reservoirs remains high. Therefore, development of alternative therapeutic options with broad-spectrum anti-coronavirus activities are urgently needed.

A deep learning model for structure-based bioactivity optimization and its application in the bioactivity optimization of a SARS-CoV-2 main protease inhibitor.

Bioactivity optimization is a crucial and technical task in the early stages of drug discovery, traditionally carried out through iterative substituent optimization, a process that is often both time-consuming and expensive. To address this challenge, we present Pocket-StrMod, a deep-learning model tailored for structure-based bioactivity optimization. Pocket-StrMod employs an autoregressive flow-based architecture, optimizing molecules within a specific protein binding pocket while explicitly incorporating chemical expertise.

Design, Synthesis, and Unprecedented Interactions of Covalent Dipeptide-Based Inhibitors of SARS-CoV-2 Main Protease and Its Variants Displaying Potent Antiviral Activity.

The main protease (M) of SARS-CoV-2 is a key drug target for the development of antiviral therapeutics. Here, we designed and synthesized a series of small-molecule peptidomimetics with various cysteine-reactive electrophiles. Several compounds were identified as potent SARS-CoV-2 M inhibitors, including compounds (IC = 0.

An orally available Mpro/TMPRSS2 bispecific inhibitor with potent anti-coronavirus efficacy in vivo.

Coronaviruses have caused three major endemics in the past two decades. Alarmingly, recent identification of novel zoonotic coronaviruses that caused human infections suggests the risk of future coronavirus outbreak caused by spillover infection from animal reservoirs remains high. Therefore, development of novel therapeutic options with broad-spectrum anti-coronavirus activities are urgently needed.

Identification of a new class of activators of the Hippo pathway with antitumor activity in vitro and in vivo.

The Hippo pathway is a key regulator of tissue growth, organ size, and tumorigenesis. Activating the Hippo pathway by gene editing or pharmaceutical intervention has been proven to be a new therapeutic strategy for treatment of the Hippo pathway-dependent cancers. To now, a number of compounds that directly target the downstream effector proteins of Hippo pathway, including YAP and TEADs, have been disclosed, but very few Hippo pathway activators are reported.

Discovery of α-Ketoamide inhibitors of SARS-CoV-2 main protease derived from quaternized P1 groups.

Although the SARS-CoV-2 pandemic has ended, multiple sporadic cases still exist, posing a request for more antivirals. The main protease (M) of SARS-CoV-2, a key enzyme for viral replication, is an attractive target for drug development. Here, we report the discovery of a new potent α-ketoamide-containing M inhibitor, N-((R)-1-cyclohexyl-2-(((R)-3-methoxy-1-oxo-1-((1-(2-oxo-2-((thiazol-2-ylmethyl)amino)acetyl)cyclobutyl)amino)propan-2-yl)amino)-2-oxoethyl)-4,4-difluorocyclohexane-1-carboxamide (20j).

Discovery and structure-activity relationship studies of novel α-ketoamide derivatives targeting the SARS-CoV-2 main protease.

The SARS-CoV-2 main protease (M, also named 3CL) is a promising antiviral target against COVID-19 due to its functional importance in viral replication and transcription. Herein, we report the discovery of a series of α-ketoamide derivatives as a new class of SARS-CoV-2 M inhibitors. Structure-activity relationship (SAR) of these compounds was analyzed, which led to the identification of a potent M inhibitor (27h) with an IC value of 10.

Discovery of benzodiazepine derivatives as a new class of covalent inhibitors of SARS-CoV-2 main protease.

The COVID-19 pandemic has caused people immense suffering all over the world. Although the World Health Organization (WHO) has announced the end of the pandemic, the sporadic virus epidemic is still ongoing and may exist permanently. Effective antivirals against SARS-CoV-2 are important to deal with the long-term threat.

Discovery of [1,2,3]Triazolo[4,5-]quinoline Derivatives as a New Class of Ataxia-Telangiectasia Mutated Kinase Inhibitors.

Ataxia-telangiectasia mutated (ATM) is an atypical serine/threonine protein kinase which is implicated in the repair of DNA double-strand breaks. Numerous reports have shown that ATM inhibition is an attractive target for radiotherapy and chemotherapy sensitization. Herein we report a new series of ATM kinase inhibitors containing the 1[1,2,3]triazolo[4,5-]quinoline scaffold, which was obtained by virtual screening, structural optimization, and structure-activity relationship studies.

A new generation M inhibitor with potent activity against SARS-CoV-2 Omicron variants.

Emerging SARS-CoV-2 variants, particularly the Omicron variant and its sublineages, continually threaten the global public health. Small molecule antivirals are an effective treatment strategy to fight against the virus. However, the first-generation antivirals either show limited clinical efficacy and/or have some defects in pharmacokinetic (PK) properties.

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 (M) is a key enzyme for SARS-CoV-2 viral replication and transcription and an attractive target for drug development.

An orally available M inhibitor is effective against wild-type SARS-CoV-2 and variants including Omicron.

Emerging SARS-CoV-2 variants continue to cause waves of new infections globally. Developing effective antivirals against SARS-CoV-2 and its variants is an urgent task. The main protease (M) of SARS-CoV-2 is an attractive drug target because of its central role in viral replication and its conservation among variants.

Discovery of 6,7-dihydro-5H-pyrrolo[3,4-d] pyrimidine derivatives as a new class of ATR inhibitors.

Ataxia telangiectasia and Rad3-related (ATR) kinase is a key regulating protein within the DNA damage response (DDR), responsible for sensing replication stress (RS), and has been considered as a potential target for cancer therapy. Herein, we report the discovery of a series of 6,7-dihydro-5H-pyrrolo[3,4-d]-pyrimidine derivatives as a new class of ATR inhibitors. Among them, compound 5g exhibits an IC value of 0.

SARS-CoV-2 M 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 (M) of SARS-CoV-2 plays a central role in viral replication. We designed and synthesized 32 new bicycloproline-containing M inhibitors derived from either boceprevir or telaprevir, both of which are approved antivirals.

Discovery of Potent Small-Molecule SIRT6 Activators: Structure-Activity Relationship and Anti-Pancreatic Ductal Adenocarcinoma Activity.

SIRT6 activation is thought to be a promising target for the treatment of many diseases, particularly cancer. Herein, we report the discovery of a series of new small-molecule SIRT6 activators. Structure-activity relationship analyses led to the identification of the most potent compound, 2-(1-benzofuran-2-yl)--(diphenylmethyl) quinoline-4-carboxamide (), which showed an EC value of 0.

Discovery of 1,8-disubstituted-[1,2,3]triazolo[4,5-c]quinoline derivatives as a new class of Hippo signaling pathway inhibitors.

Inhibitors of the Hippo signaling pathway have been demonstrated to have a potential clinical application in cases such as tissue repair and organ regeneration. However, there is a lack of potent Hippo pathway inhibitors at present. Herein we report the discovery of a series of 1,8-disubstituted-[1,2,3]triazolo[4,5-c]quinoline derivatives as a new class of Hippo pathway inhibitors by utilizing a cell line-based screening model (A549-CTGF).

Analysis of TTSuV1b antibody in porcine serum and its correlation with four antibodies against common viral infectious diseases.

Background: The purpose of the present study was to evaluate the correlation between Torque teno sus virus 1b (TTSuV1b) infection and other viral infections or vaccine immunization in conventional pigs.

Methods: With overexpressed and purified viral protein TTSuV1b as antigen, an indirect enzyme-linked immunosorbent assay (ELISA) method for detecting TTSuV1b antibody was established, which demonstrated great specificity and reproducibility. Porcine serum samples (n = 212) were tested using ELISA.