A5091145034- RNA Interference and Gene Delivery
- Renal cell carcinoma treatment
- Renal and related cancers
- Advanced biosensing and bioanalysis techniques
- Enzyme Structure and Function
- Epigenetics and DNA Methylation
- Hepatitis B Virus Studies
- Virus-based gene therapy research
- Protein Structure and Dynamics
- Cancer, Hypoxia, and Metabolism
- Cellular Mechanics and Interactions
- RNA modifications and cancer
- Lipid Membrane Structure and Behavior
- Coagulation, Bradykinin, Polyphosphates, and Angioedema
- Graphene and Nanomaterials Applications
- Immunotherapy and Immune Responses
- Biotin and Related Studies
- Protein Degradation and Inhibitors
- Cancer, Lipids, and Metabolism
- Ferroptosis and cancer prognosis
- Lipoproteins and Cardiovascular Health
- Biochemical and Molecular Research
- Ubiquitin and proteasome pathways
- DNA and Nucleic Acid Chemistry
- Bacteriophages and microbial interactions
Institut Curie
2024
Université de Montpellier
2019-2023
Centre National de la Recherche Scientifique
2019-2023
McGill University
2019-2023
Arrowhead Pharmaceuticals (United States)
2012-2016
Mirus Bio (United States)
2002-2009
University of Wisconsin–Madison
1996-2005
University of Utah
1997-2000
Northern Arizona University
1992
Achieving efficient in vivo delivery of siRNA to the appropriate target cell would be a major advance use RNAi gene function studies and as therapeutic modality. Hepatocytes, key parenchymal cells liver, are particularly attractive type for given their central role several infectious metabolic disorders. We have developed vehicle hepatocytes both vitro vivo, which we named Dynamic PolyConjugates. Key features PolyConjugate technology include membrane-active polymer, ability reversibly mask...
RNA interference (RNAi)-based therapeutics have the potential to treat chronic hepatitis B virus (HBV) infection in a fundamentally different manner than current therapies. Using RNAi, it is possible knock down expression of viral RNAs including pregenomic from which replicative intermediates are derived, thus reducing load, and proteins that result disease impact immune system's ability eliminate virus. We previously described use polymer-based Dynamic PolyConjugate (DPC) for targeted...
ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTArtificial Chaperones: Protein Refolding via Sequential Use of Detergent and CyclodextrinDavid Rozema Samuel H. GellmanCite this: J. Am. Chem. Soc. 1995, 117, 8, 2373–2374Publication Date (Print):March 1, 1995Publication History Published online1 May 2002Published inissue 1 March 1995https://pubs.acs.org/doi/10.1021/ja00113a036https://doi.org/10.1021/ja00113a036research-articleACS PublicationsRequest reuse permissionsArticle...
Conditions that promote renaturation of an unfolded protein also aggregation, in many cases, because these competing intramolecular and intermolecular processes are driven by similar networks noncovalent interactions. The GroEL/GroES system related biological chaperones facilitate the substrate proteins minimizing aggregation pathway. We have devised a two-step method which small molecules, "artificial chaperones," refolding from chemically denatured state. In first step, is captured...
Endosomolysis, a critical barrier to efficient delivery of macromolecules such as nucleic acids, has been breached using novel approach: endosomolysis by masking membrane-active agent (EMMA). To demonstrate the concept EMMA, cationic peptide, melittin, was reversibly inhibited maleic anhydride derivative. At neutral pH, lysines melittin are covalently acylated with anhydride, thereby inhibiting melittin's membrane disruption activity. Under acidic conditions those present within endosomes,...
Effective in vivo delivery of small interfering (siRNA) has been a major obstacle the development RNA interference therapeutics. One first attempts to overcome this utilized intravenous injection cholesterol-conjugated siRNA (chol-siRNA). Although studies mice revealed target gene knockdown liver, was relatively inefficient, requiring 3 daily injections 50 mg/kg chol-siRNA obtain measurable reduction expression. Here we present new approach that increases efficacy over 500-fold and allows...
The power of genetic engineering methods, along with increasing genomic information, makes heterologous expression proteins an extremely important biochemical tool. Unfortunately, obtained in this way often are not their native form, and folding becomes a crucial step protein production. We have recently developed strategy that promotes the chemically denatured via sequential addition low molecular weight "artificial chaperones." Here we describe detail application method to porcine heart...
Many proteins that contain a carboxyl-terminal CaaX sequence motif, including Ras and yeast a-factor, undergo series of sequential posttranslational processing steps. Following the initial prenylation cysteine, three C-terminal amino acids are proteolytically removed, newly formed prenylcysteine is carboxymethylated. The specific comprise influence whether protein can be prenylated proteolyzed. In this study, we evaluated a-factor variants with all possible single acid substitutions at...
The safe and efficacious delivery of membrane impermeable therapeutics requires cytoplasmic access without the toxicity nonspecific lysis. We have developed a mechanism for control release which utilizes endogenous proteases as trigger results in functional small interfering RNA (siRNA). approach is based on reversible inhibition disruptive polymers with protease-sensitive substrates. Proteolytic hydrolysis upon endocytosis restores destabilizing activity thereby allowing co-delivered siRNA....
Cationic membrane disruptive peptides such as melittin would appear to have attributes necessary for DNA delivery: binding via electrostatic interactions and lysis enable cytoplasmic delivery. However, the relatively small overall charge of results in weak with DNA. As a model cationic peptides, amphiphilic polyvinyl ethers were synthesized. The number positively charged groups incorporated into these polymers is substantially greater than membrane-active which enables form stable complexes...
Targeted therapy against VEGF and mTOR pathways has been established as the standard-of-care for metastatic clear cell renal carcinoma (ccRCC); however, these treatments frequently fail most patients become refractory requiring subsequent alternative therapeutic options. Therefore, development of innovative effective is imperative. About 80%-90% ccRCC tumors express an inactive mutant form von Hippel-Lindau protein (pVHL), E3 ubiquitin ligase that promotes target degradation. Strong genetic...
Collective migration of cohesive tissues is a fundamental process in morphogenesis and particularly well illustrated during gastrulation by the rapid massive internalization mesoderm, which contrasts with much more modest movements ectoderm. In Xenopus embryo, differences morphogenetic capabilities ectoderm mesoderm can be connected to intrinsic motility individual cells, very low for ectoderm, high mesoderm. Surprisingly, we find that these seemingly deep accounted simply Rho-kinases...
A series of lysine-based oligomers (18 residues) that differ in side chain configuration or spacing along the backbone was tested for DNA transfection activity. Although materials constructed from lysine are not most effective polymeric agents, we have chosen L-lysine-based molecules as a starting point because this system allows us to examine functional effects incremental changes polycation structure. The oligomer beta(3)-homolysine (beta(3)-hLys) and alpha-D-lysine were superior an...
Protein farnesyltransferase (PFTase) is a zinc metalloenzyme that catalyzes the posttranslational alkylation of cysteine in C-terminal −Ca1a2X sequences by 15-carbon farnesyl residue, where C cysteine, a1 and a2 are normally aliphatic amino acids, X an acid specifies selectivity for moiety. Formation Zn2+ thiolate PFTase·peptide complex was detected appearance absorbance at 236 nm (ε = 15 000 M-1cm-1), which dependent on concentration peptide, UV difference spectrum solution PFTase peptide...
The RNA interference (RNAi)-based therapeutic ARC-520 for chronic hepatitis B virus (HBV) infection consists of a melittin-derived peptide conjugated to N-acetylgalactosamine hepatocyte targeting and endosomal escape, cholesterol-conjugated RNAi triggers, which together result in HBV gene silencing. To characterize the kinetics trigger delivery 5΄-phosphorylation guide strands correlating with knockdown, we employed peptide-nucleic acid (PNA) hybridization assay. A fluorescent sense strand...
Protein prenyltransferases catalyze the posttranslational modification of cysteines by isoprenoid hydrocarbon chains. A protein farnesyltransferase (PFTase) and a geranylgeranyltransferase (PGGTase-I) alkylate in CaaX C-terminal tetrapeptide sequence, where is usually an aliphatic amino acid X that specifies whether C15 farnesyl or C20 geranylgeranyl moiety added. third enzyme, PGGTase-II, adds groups to both at C-terminus Rab proteins. All three enzymes are Zn2+ metalloproteins also require...
ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTPhotochemistry of 1-alkoxy- and 1-(benzyloxy)-9,10-anthraquinones in methanol: a .delta.-hydrogen atom abstraction process that exhibits captodative effectRonald L. Blankespoor, Randall De Jong, Robert Dykstra, Daniel A. Hamstra, David B. Rozema, Derek P. VanMeurs, Paul VinkCite this: J. Am. Chem. Soc. 1991, 113, 9, 3507–3513Publication Date (Print):April 1, 1991Publication History Published online1 May 2002Published inissue 1 April...
The blastocyst forms during the first days of mammalian development. structure is conserved among placental mammals and paramount to establishment lineages. composed an extraembryonic epithelium, trophectoderm (TE), that envelopes a fluid-filled lumen inner cell mass (ICM). To shape blastocyst, embryos transit through three stages driven by forces have been characterized in mouse embryo over past decade. morphogenetically quiescent cleavage mask dynamic cytoskeletal remodeling. Then,...
A critical step for liver-directed gene therapy is the selective targeting of nucleic acids to hepatocytes. We have previously discovered that proximal half T7 phage tail fiber protein (p17) targeted intact and recombinant proteins hepatocytes in vivo. In present study, we localized activities a 33 amino acid sequence within p17 coiled-coil rod domain. Given domain from which peptide was derived may form alpha triple helical structures, biophysical studies (CD spectra analytical...
Abstract A fundamental aspect of morphogenesis is the capacity cells to actively exchange neighbours while maintaining overall cohesion tissue. These cell rearrangements require dynamic remodelling cadherin adhesions. Many studies have examined this process in tissues where it driven by joint action protrusions and actomyosin contraction along shrinking junction. However, can also occur through differential migration. This mode rearrangement, characteristic mesenchymal tissues, much less...