Phillip P. Sharp
A5028002571- X-ray Diffraction in Crystallography
- Crystallization and Solubility Studies
- Ubiquitin and proteasome pathways
- Protein Degradation and Inhibitors
- Monoclonal and Polyclonal Antibodies Research
- Multiple Myeloma Research and Treatments
- Computational Drug Discovery Methods
- Immune Cell Function and Interaction
- Catalytic Alkyne Reactions
- Cyclopropane Reaction Mechanisms
- Glycosylation and Glycoproteins Research
- interferon and immune responses
- Asymmetric Synthesis and Catalysis
- Carbohydrate Chemistry and Synthesis
- Cancer Research and Treatments
- Genomics and Phylogenetic Studies
- Acute Lymphoblastic Leukemia research
- Peptidase Inhibition and Analysis
- RNA and protein synthesis mechanisms
- Catalytic C–H Functionalization Methods
- Marine Sponges and Natural Products
- vaccines and immunoinformatics approaches
- Synthetic Organic Chemistry Methods
- SARS-CoV-2 and COVID-19 Research
- Cancer Immunotherapy and Biomarkers
University of California, San Francisco
2018-2023
Walter and Eliza Hall Institute of Medical Research
2013-2023
Merck & Co., Inc., Rahway, NJ, USA (United States)
2021
The University of Melbourne
2013-2019
Australian National University
2006-2019
Weatherford College
2013
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...
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...
Intracellular nucleotide binding and oligomerization domain (NOD) receptors recognize antigens including bacterial peptidoglycans initiate immune responses by triggering the production of pro-inflammatory cytokines through activating NF-κB MAP kinases. Receptor interacting protein kinase 2 (RIPK2) is critical for NOD-mediated activation cytokine production. Here we develop characterize a selective RIPK2 inhibitor, WEHI-345, which delays ubiquitylation downstream NOD engagement. Despite only...
Abstract Osteosarcoma (OS) survival rates have plateaued in part due to a lack of new therapeutic options. Here we demonstrate that bromodomain inhibitors (BETi), JQ1, I-BET151, I-BET762, exert potent anti-tumour activity against primary and established OS cell lines, mediated by inhibition BRD4. Strikingly, unlike previous observations long-term human the antiproliferative JQ1 cells was driven induction apoptosis, not cycle arrest. In further contrast, independently MYC downregulation. We...
Preventing the biogenesis of disease-relevant proteins is an attractive therapeutic strategy, but attempts to target essential protein factors have been hampered by excessive toxicity. Here we describe KZR-8445, a cyclic depsipeptide that targets Sec61 translocon and selectively disrupts secretory membrane in signal peptide-dependent manner. KZR-8445 potently inhibits secretion pro-inflammatory cytokines primary immune cells highly efficacious mouse model rheumatoid arthritis. A cryogenic...
Treatment of readily available o-(buta-1,3-diyn-1-yl-)-substituted N-aryl ureas such as 1 with the Au(I)-catalyst 11 affords, via a twofold cyclization process, isomeric pyrimido[1,6-a]indol-1(2H)-one 3 in good yield.
We describe the synthesis and incorporation of α- β-configured rhamnosyl arginine cassettes into <italic>Pseudomonas aeruginosa</italic> elongation factor P-derived glycopeptides. These were used to unequivocally determine native anomeric configuration rhamnose moiety in EF-P.
A number of diazepines are known to inhibit bromo- and extra-terminal domain (BET) proteins. Their BET inhibitory activity derives from the fusion an acetyl-lysine mimetic heterocycle onto diazepine framework. Herein we describe a straightforward, modular synthesis novel 1,2,3-triazolobenzodiazepines show that 1,2,3-triazole acts as effective heterocycle. Structure-based optimization this series compounds led development potent bromodomain inhibitors with excellent against leukemic cells,...
This work provides new insights into a range of acetyl-lysine mimetics as BET bromodomain inhibitors.
Abstract The complex natural products silvestrol ( 1 ) and episilvestrol 2 are inhibitors of translation initiation through binding to the DEAD‐box helicase eukaryotic factor 4A (eIF4A). Both compounds potently cytotoxic cancer cells in vitro, has demonstrated efficacy vivo several xenograft models. Here we show that limited plasma membrane permeability is metabolized liver microsomes a manner consistent with reported for . In addition, have prepared series analogues these where pseudo‐sugar...
Compounds 1–6 and 11 representing key members of the marinoquinoline family natural products, together with related marine alkaloid aplidiopsamine A (12), have been synthesized using various combinations palladium-catalyzed Ullmann cross-coupling reductive cyclization processes involving a C3-arylated pyrrole as common intermediate. These products characterized by single-crystal X-ray analyses evaluated inhibitors acetylcholinesterase (AChE) congener 2 proving to be most active.
Abstract Glucocorticoid (GC) resistance is a poor prognostic factor in T‐cell acute lymphoblastic leukaemia (T‐ALL). Interleukin‐7 (IL‐7) mediates GC via GC‐induced upregulation of IL‐7 receptor (IL‐7R) expression, leading to increased pro‐survival signalling. IL‐7R reaches the cell surface secretory pathway, so we hypothesized that inhibiting translocation into pathway would overcome resistance. Sec61 an endoplasmic reticulum (ER) channel required for insertion polypeptides ER. Here,...
Preventing the biogenesis of disease-relevant proteins is an attractive therapeutic strategy, but attempts to target essential protein factors have been hampered by excessive toxicity. Here, we describe KZR-8445, a cyclic depsipeptide that targets Sec61 translocon and selectively disrupts secretory membrane in signal peptide-dependent manner. KZR-8445 potently inhibits secretion proinflammatory cytokines primary immune cells highly efficacious mouse model rheumatoid arthritis. A cryo-EM...
The mechanism associated with the base-promoted conversion of alkoxy-substituted and ring-fused gem-dihalocyclopropanes such as 40 into annulated furans has been explored. Treatment compound potassium tert-butoxide affords a mixture 23/27 41, an outcome that suggests intermediacy slowly interconverting carbonyl ylides 42 43 undergo rapid [1,5]-electrocyclizations subsequent dehydrohalogenation to afford observed products. This proposal is supported by ab initio MO DFT calculations also...
Upgrading therapeutics calls for tighter links across scientific and engineering disciplines.