A5071335200- Malaria Research and Control
- Nuclear Structure and Function
- Mosquito-borne diseases and control
- Hippo pathway signaling and YAP/TAZ
- Monoclonal and Polyclonal Antibodies Research
- Computational Drug Discovery Methods
- Drug Transport and Resistance Mechanisms
- RNA Research and Splicing
- Retinoids in leukemia and cellular processes
- HIV/AIDS drug development and treatment
- Insect symbiosis and bacterial influences
- RNA modifications and cancer
- Peptidase Inhibition and Analysis
- Parasites and Host Interactions
- X-ray Diffraction in Crystallography
- Parasitic Infections and Diagnostics
- Mitochondrial Function and Pathology
- ATP Synthase and ATPases Research
- Crystallization and Solubility Studies
- interferon and immune responses
- Trypanosoma species research and implications
- Amoebic Infections and Treatments
- Cancer Cells and Metastasis
- Advanced Proteomics Techniques and Applications
- NF-κB Signaling Pathways
Novartis (Singapore)
2016-2021
Institute of Bioengineering and Nanotechnology
2018
Genomics Institute of the Novartis Research Foundation
2008-2017
Novartis (Switzerland)
2009-2017
HudsonAlpha Institute for Biotechnology
2007-2012
William & Mary
2004-2008
Williams (United States)
2004-2008
Délégation Paris 7
2004-2005
Université Paris Cité
2004-2005
Inserm
2005
Most malaria drug development focuses on parasite stages detected in red blood cells, even though, to achieve eradication, next-generation drugs active against both erythrocytic and exo-erythrocytic forms would be preferable. We applied a multifactorial approach set of >4000 commercially available compounds with previously demonstrated blood-stage activity (median inhibitory concentration < 1 micromolar) identified chemical scaffolds potent forms. From this screen, we an imidazolopiperazine...
Mitochondrial dynamics: An image-based screen identified a small molecule, M1, that specifically promotes the fusion of fragmented mitochondria and protects cells from mitochondrial-fragmentation-associated cell death. Mechanistic studies revealed M1 shifts mitochondrial dynamic balance towards (see picture).
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...
Decoquinate has single-digit nanomolar activity against in vitro blood stage Plasmodium falciparum parasites, the causative agent of human malaria. In evolution decoquinate-resistant parasites and subsequent comparative genomic analysis to drug-sensitive parental strain revealed resistance was conferred by two nonsynonymous single nucleotide polymorphisms gene encoding cytochrome b. The resultant amino acid mutations, A122T Y126C, reside within helix C ubiquinol-binding pocket b, an...
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...
Plasmodium liver hypnozoites, which cause disease relapse, are widely considered to be the last barrier towards malaria eradication. The biology of this quiescent form parasite is poorly understood hinders drug discovery. We report a comparative transcriptomic dataset replicating schizonts and dormant hypnozoites relapsing cynomolgi. Hypnozoites express only 34% physiological pathways, while 91% expressed in schizonts. Few known targets parasites, but pathways involved microbial dormancy,...
Emerging evidence suggests that some cancers contain a population of stem-like TICs (tumor-initiating cells) and eliminating may offer new strategy to develop successful anti-cancer therapies. As molecular mechanisms underlying the maintenance TIC pool are poorly understood, development TIC-specific therapeutics remains major challenge. We first identified characterized non-TICs isolated from mouse breast cancer model. displayed increased tumorigenic potential, self-renewal, heterogeneous...
Many proteins or other biological macromolecules are localized to more than one subcellular structure. The fraction of a protein in different cellular compartments is often measured by colocalization with organelle-specific fluorescent markers, requiring availability probes for each compartment and acquisition images conjunction the macromolecule interest. Alternatively, tailored algorithms allow finding particular regions quantifying amount fluorescence they contain. Unfortunately, this...
The thyroid hormone receptor alpha1 (TRalpha) exhibits a dual role as an activator or repressor of its target genes in response to (T(3)). Previously, we have shown that TRalpha, formerly thought reside solely the nucleus bound DNA, actually shuttles rapidly between and cytoplasm. An important aspect shuttling activity TRalpha is ability exit through nuclear pore complex. export not sensitive treatment with CRM1-specific inhibitor leptomycin B (LMB) heterokaryon assays, suggesting for other...
Previously, FRET confocal microscopy has shown that polymeric IgA-receptor (pIgA-R) is distributed in a clustered manner apical endosomes. To test whether different membrane-bound components form clusters during membrane trafficking, live-cell quantitative was used to characterize the organization of pIgA-R and transferrin receptor (TFR) endocytic membranes polarized MDCK cells upon internalization donor- acceptor-labeled ligands. We show TFR complexes increasingly organized cotransport from...
Abstract Malaria control and elimination are threatened by the emergence spread of resistance to artemisinin-based combination therapies (ACTs). Experimental evidence suggests that when an artemisinin (ART)-sensitive (K13 wild-type ) Plasmodium falciparum strain is exposed ART derivatives such as dihydroartemisinin (DHA), a small population early ring-stage parasites can survive drug treatment entering cell cycle arrest or dormancy. After removal, these resume growth. Dormancy has been...
The drug HD201 is a biosimilar candidate for breast cancer treatment as the reference trastuzumab.
Abstract The retroviral v-ErbA oncoprotein is a highly mutated variant of the thyroid hormone receptor α (TRα), which unable to bind T3 and interferes with action TRα in mammalian avian cancer cells. dominant-negative activity attributed competition for T3-responsive DNA elements and/or auxiliary factors involved transcriptional regulation genes. However, models do not address altered subcellular localization its possible implications oncogenesis. Here, we report that dimerizes retinoid X...
Nuclear receptors (NRs) are transcription factors whose activity is modulated by ligand binding. These at the core of complex signaling pathways and act as integrators many cellular signals. In last decade our understanding NRs has greatly evolved. particular, regulation NR subcellular dynamics emerged central to their activity. Research on distribution thyroid hormone receptor (TR) revealed new dimensions in complexity regulation, points possibility that mislocalization plays a key role...
Artemisinin (ART) resistance has spread through Southeast Asia, posing a serious threat to the control and elimination of malaria. ART been associated with mutations in Plasmodium falciparum kelch-13 (Pfk13) propeller domain. Phenotypically, is defined as delayed parasite clearance patients due reduced susceptibility early ring-stage parasites active metabolite dihydroartemisinin (DHA). Early rings can enter state quiescence upon DHA exposure resume growth its absence. These quiescent are...
v-ErbA, an oncogenic derivative of the thyroid hormone receptor α (TRα) carried by avian erythroblastosis virus, contains several alterations including fusion a portion virus Gag to its N terminus, N- and C-terminal deletions, 13 amino acid substitutions. Nuclear export v-ErbA occurs through CRM1-mediated pathway. In contrast, nuclear TRα another isoform, TRβ, is CRM1-independent. To determine which changes in confer CRM1-dependent export, we expressed panel green yellow fluorescent...
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...