RiboxX GmbH | Date: 2015-03-24
Double-stranded ribonucleic acids (dsRNA) of at least 45 bp, preferably of at least 50 bp, which dsRNA include at least one 5-triphosphate group and further includes at least one chemical modification at a 5 end, at a 3 end and/or at a non-terminal nucleotide. The invention further provides pharmaceutical compositions containing such modified dsRNAs, methods for their production, and to their use in medicine, in particular for immunostimulation and treatment as well as prevention of infectious, autoimmune, degenerative, cancer and tumor diseases.
Tarantino D.,University of Milan |
Pezzullo M.,University of Milan |
Pezzullo M.,CNR Institute of Biophysics |
Mastrangelo E.,University of Milan |
And 8 more authors.
Antiviral Research | Year: 2014
Noroviruses are members of the Caliciviridae family of positive sense RNA viruses. In humans Noroviruses cause rapid onset diarrhea and vomiting. Currently Norovirus infection is responsible for 21 million gastroenteritis yearly cases in the USA. Nevertheless, despite the obvious public health and socio-economic relevance, no effective vaccines/antivirals are yet available to treat Norovirus infection. Since the activity of RNA-dependent RNA polymerase (RdRp) plays a key role in genome replication and in the synthesis/amplification of subgenomic RNA, the enzyme is considered a promising target for antiviral drug development. In this context, following the identification of suramin and NF023 as Norovirus RdRp inhibitors, we analyzed the potential inhibitory role of naphthalene di-sulfonate (NAF2), a fragment derived from these two molecules. Although NAF2, tested in enzymatic polymerase inhibition assays, displayed low activity against RdRp (IC50 = 14 μM), the crystal structure of human Norovirus RdRp revealed a thumb domain NAF2 binding site that differs from that characterized for NF023/suramin. To further map the new potential inhibitory site, we focused on the structurally related molecule pyridoxal-5′-phosphate-6-(2′-naphthylazo-6′-nitro-4′, 8′-disulfonate) tetrasodium salt (PPNDS). PPNDS displayed below-micromolar inhibitory activity versus human Norovirus RdRp (IC50 = 0.45 μM), similarly to suramin and NF023. Inspection of the crystal structure of the RdRp/PPNDS complex showed that the inhibitor bound to the NAF2 thumb domain site, highlighting the relevance of such new binding site for exploiting Norovirus RdRp inhibitors. © 2013 Elsevier B.V. All rights reserved.
Agency: European Commission | Branch: FP7 | Program: CP-IP | Phase: HEALTH.2010.2.3.3-2 | Award Amount: 21.90M | Year: 2010
RNA virus infections kill millions of humans annually, largely due to the lack of suitable vaccines and drugs to control them. This problem is addressed in this FP7 call and in response a consortium of Europes and Asias leading molecular virologists, structural biologists, medicinal chemists and bioinformaticians has been brought together to generate a state-of-the-art drug discovery and design programme. The project aims to identify Small molecule Inhibitor Leads Versus Emerging and neglected RNA viruses (SILVER). It will focus its activities on selected medically important RNA viruses for which the development of drugs is considered essential (Dengue-, entero- and paramyxoviruses), whereas other relatively neglected and/or emerging RNA viruses will be explored to identify the most promising viral protein targets and antiviral compounds. A pipeline strategy has been developed to enable the inclusion in SILVER of viruses at all levels of existing knowledge. Targets for potential drugs include infectious virus, structurally characterised viral enzymes and other proteins. Leads for currently available antiviral drugs have been identified by screening compound libraries in virus-infected cell culture systems and in vitro assays using purified viral enzymes. Selective inhibitors of viral replication have also been (and are being) derived using detailed structural knowledge of viral proteins and structure-based drug design. Hits will be assayed using individual viral protein targets and replicative proteins in complex with viral RNA. The potential protective activity of the most potent inhibitors, that have a favourable (in vitro) ADME-tox profile, will be assessed in relevant infection models in animals. Licenses on promising compounds or compound classes will be presented to the interested pharmaceutical industry. The SILVER consortium will be well placed to play a major role in contributing to the international effort to develop strategies to improve world health.
Agency: European Commission | Branch: FP7 | Program: MC-ITN | Phase: FP7-PEOPLE-2010-ITN | Award Amount: 4.98M | Year: 2011
Virus infections remain a major cause of disease, with dramatic costs in mortality, morbidity, and economic loss worldwide. There is an unmet need for potent antiviral drugs, in particular against viruses with a (\)RNA genome which include many important pathogens of humans and animals. Antiviral drug development requires a detailed understanding of virus replication and effective translation of this knowledge into drug discovery. Europe needs well-trained experts with multidisciplinary skills to advance this field. However, few, if any, European training institutes have the broad know-how required to provide such a comprehensive training programme. The EUVIRNA partnership aims to fill this gap with the proposed EUVIRNA training programme. The EUVIRNA partnership consists of six outstanding European academic partners and four industrial partners (one pharmaceutical R&D company and three SMEs), and an associated partner (SME specialized in education). All EUVIRNA partners are recognized leaders in their field, ensuring state-of-the-art training possibilities, and their skills are highly complementary. Three Visiting Researchers will complement the expertise of the partners. EUVIRNA aims to introduce 18 ESRs and 2 ERs to state-of-the-art knowledge and technology applied in molecular virology and antiviral therapy, with both local and network-wide training activities. Individual research projects, research training workshops and intersectoral secondments will be supplemented with complementary skills courses to improve career development and perspectives. The industrial partners are actively involved in the entire programme, and will furthermore organize a 1-week industry-oriented conference aimed at further bridging the gap between academia and industry. Thus, EUVIRNA offers talented researchers a multidisciplinary and intersectoral training programme and prepares them for a future leading role in European molecular virology research and antiviral dru
RiboxX GmbH | Date: 2010-10-21
The present invention relates to a method for exponential amplification of RNA using a primer independent RNA-dependent RNA polymerase (RdRp) wherein reactants are premixed cycle and then transferred into the reaction chamber in which the steps of polymerisation of the complementary strand and separation of the resulting double-stranded RNA occur. The invention also relates to a RNA reactor for carrying out the exponential RNA amplification.
RiboxX GmbH | Date: 2010-10-21
The present invention relates to a method for exponential amplification of RNA in vitro by using a thermostable RNA-dependent RNA polymerase (RdRp) of a sapovirus or norovirus.
RiboxX GmbH | Date: 2014-12-16
The present invention relates to polyC:poly(G/1) dsRNAs for triggering innate immunity, in particular through toll-like receptor 3 (TLR-3) and, optionally, RIG-I or RIG-Ilike receptors (RLRs), as well as compositions and medicaments containing such dsRNAs, methods for their production and their use in medicine, especially immunostimulation and prevention and/or therapy of infections and tumor diseases.
RiboxX GmbH | Date: 2012-06-13
The present invention relates to a kit for carrying out methods for the detection of target RNA sequences making use of strand displacement techniques employing RNA-dependent RNA polymerases of viruses of the Caliciviridae family having RNA-oligonucleotide duplex separation activity and being capable of de novo RNA synthesis in the absence of a primer.
Riboxx Gmbh | Date: 2012-10-31
The present invention relates to a ribonucleic acid (RNA) of double-stranded structure which is capable of triggering Toll-like receptor 3 (TLR-3) and which shows an increased serum stability while simultaneously being unable to be processed by the DICER complex.
Riboxx Gmbh | Date: 2010-02-24
The present invention relates to small-interfering RNA molecules displaying an increased thermodynamic stability at the 3 end of the antisense strand (guide strand) and the 5 end of the sense strand (passenger strand), respectively, in comparison to the base pairing in the seed region. The siRNAs of the present invention display an increased knock-down activity against targeted genes and show an improved resistance to RNAses, in particular serum RNAses. The present invention also relates to a method for the production of the siRNA molecules, a method of target-specific RNA interference making use of the improved siRNA molecules of the invention and pharmaceutical compositions containing the siRNA molecules.