Identification of a methylated oligoribonucleotide as a potent inhibitor of HIV-1 reverse transcription complex

Upon HIV-1 infection of a target cell, the viral reverse transcriptase (RT) copies the genomic RNA to synthesize the viral DNA. The genomic RNA is within the incoming HIV-1 core where it is coated by molecules of nucleocapsid (NC) protein that chaperones the reverse transcription process. Indeed, the RT chaperoning properties of NC extend from the initiation of cDNA synthesis to completion of the viral DNA. New and effective drugs against HIV-1 continue to be required, which prompted us to search for compounds aimed at inhibiting NC protein. Here, we report that the NC chaperoning activity is extensively inhibited in vitro by small methylated oligoribonucleotides (mODN). These mODNs were delivered intracellularly using a cell-penetrating-peptide and found to impede HIV-1 replication in primary human cells at nanomolar concentrations. Extensive analysis showed that viral cDNA synthesis was severely impaired by mODNs. Partially resistant viruses with mutations in NC and RT emerged after months of passaging in cell culture. A HIV-1 molecular clone (NL4.3) bearing these mutations was found to replicate at high concentrations of mODN, albeit with a reduced fitness. Small, methylated ODNs such as mODN-11 appear to be a new type of highly potent inhibitor of HIV-1

Etude spectroscopique et photophysique du transfert electronique intramoleculaire dans des composes de coordination. Implications pour l'electronique moleculaire

SIGLEINIST T 77104 / INIST-CNRS - Institut de l'Information Scientifique et TechniqueFRFranc

PEOCOC project C1 doped G1 EO polymer preliminary characteristics

SIGLEAvailable from INIST (FR), Document Supply Service, under shelf-number : AR 16485 (1); AR 16485 (2) / INIST-CNRS - Institut de l'Information Scientifique et TechniqueMinistere de la Recherche et de l'Espace (MRE), 75 - Paris (France)FRFranc

Radiolabeling of magnetic targeted carriers (MTC) with indium-111

Abstract Magnetic targeted carriers (MTC) are magnetically susceptible microparticles that can be physically targeted to a specific site. MTC were radiolabeled with 111 In using three different methods. Reaction parameters were investigated in order to optimize the final properties of the labeled MTC. The reaction parameters studied were chelation agent, chelation time, temperature, radiolabeling time, solvent, and molar ratios. A 97.7 Ϯ 0.9% binding efficiency and plasma stability of 92.6 Ϯ 0.1% over 7 days were achieved when 2-p-aminobenzyl-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetra-acetic acid (ABz-DOTA) was used as the chelating agent. A preliminary animal biodistribution study confirmed the binding stability. The labeling of the MTC with the diagnostic isotope 111 In was undertaken to allow for quantitative imaging and dosimetry prior to therapy with 90 Y radiolabeled MTC

Radiolabeling of magnetic targeted carriers (MTC) with indium-111

Abstract Magnetic targeted carriers (MTC) are magnetically susceptible microparticles that can be physically targeted to a specific site. MTC were radiolabeled with 111 In using three different methods. Reaction parameters were investigated in order to optimize the final properties of the labeled MTC. The reaction parameters studied were chelation agent, chelation time, temperature, radiolabeling time, solvent, and molar ratios. A 97.7 Ϯ 0.9% binding efficiency and plasma stability of 92.6 Ϯ 0.1% over 7 days were achieved when 2-p-aminobenzyl-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetra-acetic acid (ABz-DOTA) was used as the chelating agent. A preliminary animal biodistribution study confirmed the binding stability. The labeling of the MTC with the diagnostic isotope 111 In was undertaken to allow for quantitative imaging and dosimetry prior to therapy with 90 Y radiolabeled MTC

Therapeutic targeting of PFKFB3 with a novel glycolytic inhibitor PFK158 promotes lipophagy and chemosensitivity in gynecologic cancers.

Metabolic alterations are increasingly recognized as important novel anti-cancer targets. Among several regulators of metabolic alterations, fructose 2,6 bisphosphate (F2,6BP) is a critical glycolytic regulator. Inhibition of the active form of PFKFB3ser461 using a novel inhibitor, PFK158 resulted in reduced glucose uptake, ATP production, lactate release as well as induction of apoptosis in gynecologic cancer cells. Moreover, we found that PFK158 synergizes with carboplatin (CBPt) and paclitaxel (PTX) in the chemoresistant cell lines, C13 and HeyA8MDR but not in their chemosensitive counterparts, OV2008 and HeyA8, respectively. We determined that PFK158-induced autophagic flux leads to lipophagy resulting in the downregulation of cPLA2, a lipid droplet (LD) associated protein. Immunofluorescence and co-immunoprecipitation revealed colocalization of p62/SQSTM1 with cPLA2 in HeyA8MDR cells uncovering a novel pathway for the breakdown of LDs promoted by PFK158. Interestingly, treating the cells with the autophagic inhibitor bafilomycin A reversed the PFK158-mediated synergy and lipophagy in chemoresistant cells. Finally, in a highly metastatic PTX-resistant in vivo ovarian mouse model, a combination of PFK158 with CBPt significantly reduced tumor weight and ascites and reduced LDs in tumor tissue as seen by immunofluorescence and transmission electron microscopy compared to untreated mice. Since the majority of cancer patients will eventually recur and develop chemoresistance, our results suggest that PFK158 in combination with standard chemotherapy may have a direct clinical role in the treatment of recurrent cancer