A5029354259- Mosquito-borne diseases and control
- Malaria Research and Control
- Cell death mechanisms and regulation
- Insect symbiosis and bacterial influences
- Viral Infections and Vectors
- Retinal Development and Disorders
- Phosphodiesterase function and regulation
- Berberine and alkaloids research
- HIV Research and Treatment
- Crystallization and Solubility Studies
- Synthesis and Biological Activity
- Receptor Mechanisms and Signaling
- Autophagy in Disease and Therapy
- X-ray Diffraction in Crystallography
- Endoplasmic Reticulum Stress and Disease
- Clusterin in disease pathology
- Parasitic Infections and Diagnostics
- Parasites and Host Interactions
- Bioactive Compounds and Antitumor Agents
- DNA and Nucleic Acid Chemistry
- Amoebic Infections and Treatments
- interferon and immune responses
- Trypanosoma species research and implications
- Bacteriophages and microbial interactions
- Pancreatitis Pathology and Treatment
Agency for Science, Technology and Research
2008-2025
Experimental Drug Development Centre
2009-2025
Novartis (Singapore)
2014-2023
Novartis (Switzerland)
2015
Institute of Molecular and Cell Biology
2006-2010
University of Strathclyde
2001-2005
Flaviviruses comprise major emerging pathogens such as dengue virus (DENV) or Zika (ZIKV). The flavivirus RNA genome is replicated by the RNA-dependent-RNA polymerase (RdRp) domain of non-structural protein 5 (NS5). This essential enzymatic activity renders RdRp attractive for antiviral therapy. NS5 synthesizes viral via a "de novo" initiation mechanism. Crystal structures revealed "closed" conformation reminiscent pre-initiation state, with well ordered priming loop that extrudes from thumb...
The four serotypes of dengue virus (DENV-1 to -4) represent the most prevalent mosquito-borne viral pathogens in humans. No clinically approved vaccine or antiviral is currently available for DENV. Here we report a spiropyrazolopyridone compound that potently inhibits DENV both vitro and vivo. inhibitor was identified through screening 1.8-million-compound library by using DENV-2 replicon assay. selectively -3 (50% effective concentration [EC50], 10 80 nM) but not DENV-1 -4 (EC50,>20 M)....
Dengue virus (DENV) is a mosquito-borne flavivirus that poses threat to public health, yet no antiviral drug available. We performed high-throughput phenotypic screen using the Novartis compound library and identified candidate chemical inhibitors of DENV. This series was optimized improve properties such as anti-DENV potency solubility. The lead compound, NITD-688, showed strong against all four serotypes DENV demonstrated excellent oral efficacy in infected AG129 mice. There 1.44-log...
Millions who live in Latin America and sub-Saharan Africa are at risk of trypanosomatid infections, which cause Chagas disease human African trypanosomiasis (HAT). Improved HAT treatments available, but therapies rely on two nitroheterocycles, suffer from lengthy drug regimens safety concerns that frequent treatment discontinuation. We performed phenotypic screening against trypanosomes identified a class cyanotriazoles (CTs) with potent trypanocidal activity both vitro mouse models HAT....
Flavivirus infections by Zika and dengue virus impose a significant global healthcare threat with no US Food Drug Administration (FDA)-approved vaccination or specific antiviral treatment available. Here, we present the discovery of an anti-flaviviral natural product named cavinafungin. Cavinafungin is potent selectively active compound against all four serotypes. Unbiased, genome-wide genomic profiling in human cells using novel CRISPR/Cas9 protocol identified...
Spiropyrazolopyridone 1 was identified, as a novel dengue virus (DENV) inhibitor, from DENV serotype 2 (DENV-2) high-throughput phenotypic screen. As general trend within this chemical class, chiral resolution of the racemate revealed that R enantiomer significantly more potent than S. Cell-based lead optimization spiropyrazolopyridones focusing on improving physicochemical properties is described. result, an optimal compound 14a, with balanced in vitro potency and pharmacokinetic profile,...
Rationale: Acute pancreatitis (AP) is a common gastrointestinal disease affecting nearly 3 million people annually worldwide. Although AP typically self-limiting, up to 20% of patients may develop life-threatening complications. Individuals who suffer from also have an increased likelihood developing other exocrine and endocrine pancreatic disorders. However, date, there are no specific, targeted treatment modalities that can effectively improve the clinical outcomes AP. Leucine-rich alpha-2...
We have shown previously that LPPs (lipid phosphate phosphatases) reduce the stimulation of p42/p44 MAPK (p42/p44 mitogen-activated protein kinase) pathway by GPCR (G-protein-coupled receptor) agonists S1P (sphingosine 1-phosphate) and LPA (lysophosphatidic acid) in serum-deprived HEK-293 cells [Alderton, Darroch, Sambi, McKie, Ahmed, N. J. Pyne S. (2001) Biol. Chem. 276, 13452-13460]. In present study, we now show this can be blocked pretreating with caspase 3/7 inhibitor, Ac-DEVD-CHO...
Abstract: Dengue virus (DENV) protease is an attractive target for drug development; however, no compounds have reached clinical development to date. In this study, we utilized a potent West Nile inhibitor of the pyrazole ester derivative class as chemical starting point DENV development. Compound potency and selectivity were improved through structure-guided small molecule optimization, protease-inhibitor binding interactions validated biophysically using nuclear magnetic resonance. Our...
Dengue virus (DENV) is the most significant mosquito-borne viral pathogen in world and cause of dengue fever. The DENV RNA-dependent RNA polymerase (RdRp) conserved among four serotypes an attractive target for antiviral drug development. During initiation synthesis, switches from a "closed" to "open" conformation accommodate template. Inhibitors that lock or block would prevent synthesis. Herein, we describe screening campaign employed two biochemical assays identify inhibitors RdRp...
AbstractSince apoptosis is impaired in malignant cells overexpressing prosurvival Bcl-2 proteins, drugs mimicking their natural antagonists, BH3-only might overcome chemoresistance. Small molecule inhibitors of Bcl-XL function have been discovered from diverse structure classes using rational drug design as well high-throughput screening (HTS) approaches. However, most the BH3 mimetics that identified via based on fluorescence polarization displayed an affinity for presumed protein targets...
The inhibitory γ subunit of the retinal photoreceptor type 6 cGMP phosphodiesterase (PDEγ) is phosphorylated by G-protein-coupled receptor kinase 2 on threonine 62 and regulates epidermal growth factor- dependent stimulation p42/p44 mitogen-activated protein in human embryonic kidney 293 cells. We report here that PDEγ a pre-formed complex with c-Src cells factor promotes association GRK2 this complex. has critical role cascade factor, because inhibitors block activation factor. Mutation...
The inhibitory γ subunits of the retinal rod and cone photoreceptor type 6 cyclic guanosine monophosphate phosphodiesterase (PDEγ) are expressed in non-retinal tissues. Here, we show that PDEγ interacts with G-protein-coupled receptor kinase 2 signaling system to regulate epidermal growth factor- thrombin-dependent stimulation p42/p44 mitogen-activated protein human embryonic kidney 293 cells. This is based upon several lines evidence. First, transfection cells an antisense plasmid...
Cryptosporidiosis is a diarrheal disease predominantly caused by Cryptosporidium parvum (Cp) and hominis (Ch), apicomplexan parasites which infect the intestinal epithelial cells of their human hosts. The only approved drug for cryptosporidiosis nitazoxanide, shows limited efficacy in immunocompromised children, most vulnerable patient population. Thus, new therapeutics vitro infection models are urgently needed to address current unmet medical need. Toward this aim, we have developed novel...