A5100357838- Protein Kinase Regulation and GTPase Signaling
- Reconstructive Surgery and Microvascular Techniques
- Crystallization and Solubility Studies
- Chemical Synthesis and Analysis
- PI3K/AKT/mTOR signaling in cancer
- Signaling Pathways in Disease
- X-ray Diffraction in Crystallography
- Carbohydrate Chemistry and Synthesis
- Reconstructive Facial Surgery Techniques
- Asymmetric Hydrogenation and Catalysis
- Analytical chemistry methods development
- SARS-CoV-2 and COVID-19 Research
- Nanomaterials for catalytic reactions
- Synthetic Organic Chemistry Methods
- Peptidase Inhibition and Analysis
- Crystallography and molecular interactions
- Asymmetric Synthesis and Catalysis
- Protein Degradation and Inhibitors
- Computational Drug Discovery Methods
- Traditional and Medicinal Uses of Annonaceae
- COVID-19 Clinical Research Studies
- Advanced biosensing and bioanalysis techniques
- Biochemical and Molecular Research
- Data-Driven Disease Surveillance
- Lipid Membrane Structure and Behavior
University of Missouri
2023-2025
Shandong First Medical University
2025
Shandong Provincial Institute of Dermatology and Venereology
2025
China Agricultural University
2024
University of California, San Francisco
2019-2024
Howard Hughes Medical Institute
2019-2024
Tsinghua University
2008-2024
Zunyi Medical University
2019-2024
Trinity University of Asia
2024
Peking University
2010-2024
A newly described coronavirus named severe acute respiratory syndrome 2 (SARS-CoV-2), which is the causative agent of disease 2019 (COVID-19), has infected over 2.3 million people, led to death more than 160,000 individuals and caused worldwide social economic disruption1,2. There are no antiviral drugs with proven clinical efficacy for treatment COVID-19, nor there any vaccines that prevent infection SARS-CoV-2, efforts develop hampered by limited knowledge molecular details how SARS-CoV-2...
The COVID-19 pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a grave threat to public health and the global economy. SARS-CoV-2 closely related more lethal but less transmissible coronaviruses SARS-CoV-1 Middle East (MERS-CoV). Here, we have carried out comparative viral-human protein-protein interaction viral protein localization analyses for all three viruses. Subsequent functional genetic screening identified host factors that functionally impinge on...
ABSTRACT An outbreak of the novel coronavirus SARS-CoV-2, causative agent COVID-19 respiratory disease, has infected over 290,000 people since end 2019, killed 12,000, and caused worldwide social economic disruption 1,2 . There are currently no antiviral drugs with proven efficacy nor there vaccines for its prevention. Unfortunately, scientific community little knowledge molecular details SARS-CoV-2 infection. To illuminate this, we cloned, tagged expressed 26 29 viral proteins in human...
Inhibiting mTOR may reverse TGF-β–induced metastatic traits and drug resistance in carcinoma cells.
Repurposing drugs as treatments for COVID-19, the disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has drawn much attention. Beginning with sigma receptor ligands and expanding to other from screening in field, we became concerned that phospholipidosis was a shared mechanism underlying antiviral activity of many repurposed drugs. For all 23 cationic amphiphilic tested, including hydroxychloroquine, azithromycin, amiodarone, four others already clinical trials,...
Drugs that directly impede the function of driver oncogenes offer exceptional efficacy and a therapeutic window. The recently approved mutant selective small-molecule cysteine-reactive covalent inhibitor G12C K-Ras, sotorasib, provides case in point. KRAS is most frequently mutated proto-oncogene human cancer, yet despite success targeting allele, targeted therapy for other hotspot mutants has not been described. Here we report discovery small molecules covalently target G12S somatic...
KRAS mutations are one of the most common oncogenic drivers in human cancer. While small molecule inhibitors for G12C mutant have been successfully developed, allele-specific inhibition other hotspot mutants remains challenging. Here we report discovery covalent chemical ligands K-Ras(G12R). These bind Switch II pocket and irreversibly react with arginine residue. An X-ray crystal structure reveals an imidazolium condensation product formed between α,β-diketoamide ligand ε- η-nitrogens 12....
Immunotargeting of tumor-specific antigens is a powerful therapeutic strategy. Immunotherapies directed at MHC-I complexes have expanded the scope and enabled direct targeting intracellular oncoproteins cell surface. We asked whether covalent drugs that alkylate mutated residues on could act as haptens to generate unique MHC-I-restricted neoantigens. Here, we report KRAS G12C mutant cells treated with inhibitor ARS1620 present ARS1620-modified peptides in complexes. Using ARS1620-specific...
Abstract Current small-molecule inhibitors of KRAS(G12C) bind irreversibly in the switch-II pocket (SII-P), exploiting strong nucleophilicity acquired cysteine as well preponderance GDP-bound form this mutant. Nevertheless, many oncogenic KRAS mutants lack these two features, and it remains unknown whether targeting SII-P is a practical therapeutic approach for beyond G12C. Here we use NMR spectroscopy cellular engagement assay to address question by examining collection ligands from...
K-Ras is the most commonly mutated oncogene in human cancer. The recently approved non-small cell lung cancer drugs sotorasib and adagrasib covalently capture an acquired cysteine K-Ras-G12C mutation lock it a signaling-incompetent state. However, covalent inhibition of G12D, frequent particularly prevalent pancreatic ductal adenocarcinoma, has remained elusive due to lack aspartate-targeting chemistry. Here we present set malolactone-based electrophiles that exploit ring strain crosslink...
We report the identification of three cyclic peptide ligands K-Ras(G12D) using an integrated in vitro translation–mRNA display selection platform. These peptides show preferential binding to GTP-bound state over GDP-bound and block Ras-Raf interaction. A co-crystal structure KD2 with K-Ras(G12D)·GppNHp reveals that this binds Switch II groove region concomitant opening loop a 40° rotation α2 helix, threonine residue (Thr10) on has direct access mutant aspartate (Asp12) K-Ras. Replacing...
Abstract On-target–off-tissue drug engagement is an important source of adverse effects that constrains the therapeutic window candidates 1,2 . In diseases central nervous system, drugs with brain-restricted pharmacology are highly desirable. Here we report a strategy to achieve inhibition mammalian target rapamycin (mTOR) while sparing mTOR activity elsewhere through use brain-permeable inhibitor RapaLink-1 and brain-impermeable FKBP12 ligand RapaBlock. We show this combination mitigates...
The G protein-coupled receptor cascade leading to production of the second messenger cAMP is replete with pharmacologically targetable proteins, exception Gα subunit, Gαs. GTPases remain largely undruggable given difficulty displacing high-affinity guanine nucleotides and lack other drug binding sites. We explored a chemical library 10
A novel visible-light-promoted C–P bond formation reaction in the absence of both transition metal and photoredox catalysts is disclosed. By employing easily available inexpensive heteroaryl chlorides/bromides as substrates, a variety phosphine oxides were obtained moderate to good yields. This strategy provides simple efficient route oxides.
A novel protocol for effective rhodium(I)-catalyzed C-H arylation of tertiary phosphines has been devised. It is amenable to a wide range substrates and gives the products in moderate high yields. This strategy provides simple efficient route peri-substituted (naphthalen-1-yl)phosphines.
Abstract Here we report the design, synthesis, and characterization of bifunctional chemical ligands that induce association Ras with ubiquitously expressed immunophilin proteins such as FKBP12 cyclophilin A. We show this approach is applicable to two distinct ligand scaffolds, both identity linker chemistry affect compound efficacy in biochemical cellular contexts. These bind an immunophilin‐dependent fashion mediate formation tripartite complexes Ras, immunophilin, ligand. The recruitment...
Abstract Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has resulted in millions of deaths worldwide and massive societal economic burden. Recently, a new variant SARS-CoV-2, known as B.1.1.7, was first detected the United Kingdom is spreading several other countries, heightening public health concern raising questions to resulting effectiveness vaccines therapeutic interventions. We others previously identified host-directed...
Abstract Hydrogenation of diesters to diols is a vital process for chemical industry. The inexpensive Cu + /Cu 0 ‐based catalysts are highly active the hydrogenation esters, however, how efficiently tune ratio and stabilize great challenge. In this work, it demonstrated that doped Ti ions can by TiOCu bonds in Ti‐doped SiO 2 supported nanoparticle (Cu/Ti–SiO ) high conversion dimethyl adipate 1,6‐hexanediol. synthesis catalysts, 4+ OCu 2+ promote reduction forming 3+ O V Cu (O : oxygen...
Autophagy is an essential degradation and recycling process that maintains cellular homeostasis during stress or nutrient deprivation. However, certain types of tumors such as pancreatic cancers can circumvent autophagy inhibition to sustain growth. The mechanism autophagy-deficient ductal adenocarcinoma (PDAC) uses grow under deprivation poorly understood. Our data show in PDAC results UDP-glucose dehydrogenase (UGDH) degradation, which dependent on autophagic cargo receptor sequestosome 1...