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Uppsala, Sweden

Geitmann M.,Uppsala University | Geitmann M.,Beactica AB | Dahl G.,Uppsala University | Dahl G.,Boehringer Ingelheim | Danielson U.H.,Uppsala University
Journal of Molecular Recognition | Year: 2011

The mechanism and kinetics of the interactions between ligands and immobilized full-length hepatitis C virus (HCV) genotype 1a NS3 have been characterized by SPR biosensor technology. The NS3 interactions for a series of NS3 protease inhibitors as well as for the NS4A cofactor, represented by a peptide corresponding to the sequence interacting with the enzyme, were found to be heterogeneous. It may represent interactions with two stable conformations of the protein. The NS3-NS4A interaction consisted of a high-affinity (K D = 50 nM) and a low-affinity (KD = 2 ÂμM) interaction, contributing equally to the overall binding. By immobilizing NS3 alone or together with NS4A it was shown that all inhibitors had a higher affinity for NS3 in the presence of NS4A. NS4A thus has a direct effect on the binding of inhibitors to NS3 and not only on catalysis. As predicted, the mechanism-based inhibitor VX 950 exhibited a time-dependent interaction with a slow formation of a stable complex. BILN 2061 or ITMN-191 showed no signs of time-dependent interactions, but ITMN-191 had the highest affinity of the tested compounds, with both the slowest dissociation (koff) and fastest association rate, closely followed by BILN 2061. The koff for the inhibitors correlated strongly with their NS3 protease inhibitory effect as well as with their effect on replication of viral proteins in replicon cell cultures, confirming the relevance of the kinetic data. This approach for obtaining kinetic and mechanistic data for NS3 protease inhibitor and cofactor interactions is expected to be of importance for understanding the characteristics of HCV NS3 functionality as well as for anti-HCV lead discovery and optimization. Copyright © 2010 John Wiley & Sons, Ltd.


Grant
Agency: Cordis | Branch: FP7 | Program: CP-FP | Phase: HEALTH.2010.2.3.3-4 | Award Amount: 7.82M | Year: 2010

Influenza viruses cause a highly contagious respiratory disease in both humans and animals. Typically, influenza spreads worldwide in seasonal epidemics resulting in an estimated 3 to 5 million cases of severe illness and 250,000 to 500,000 deaths annually. In addition to these seasonal epidemics there have been several pandemics since the early 1900s, where highly virulent strains emerged, the most devastating being the Spanish Flu of 1918, which caused 20-40 million deaths globally. Vaccination is currently the primary means of controlling the spread of influenza virus infections but due to the viruss notorious ability to mutate, new vaccines must be developed each year. There are a few antiviral drugs that are currently on the market; however, their therapeutic potential is restricted through rapid appearance of drug-resistant viruses during treatment. Thus, the need for novel effective drugs against influenza is evident. The FLUCURE project aims at developing innovative, first-in-class therapeutics against influenza by targeting the viral ribonucleoprotein complex, which is replication core of the virion and a major contributor to viral virulence. The high level of conservation combined with slow mutation rates of the ribonucleoprotein complex should result in therapeutics with broad viral strain specificity associated with a reduced risk for developing resistance. FLUCURE builds further on two successful EU-FP7 drug discovery projects, FLUINHIBIT and FluDrugStrategy, both targeting specific but different protein-protein interactions of the viral ribonucleoprotein complex with small molecule inhibitors. A consortium of 10 partners with the required complementary skills will progress the lead candidates from these two projects synergistically through lead optimization and preclinical development phases, with the final objective to deliver one or more drug candidates suitable for entering clinical development within 4 years.


Grant
Agency: Cordis | Branch: FP7 | Program: CP-FP | Phase: HEALTH-2007-2.3.3-1;HEALTH-2007-2.3.3-7 | Award Amount: 1.94M | Year: 2008

Objective: To find and produce novel target compounds against the influenza virus. Influenza A capsid protein is the target since it does not mutate at the same rate as the Hemagglutinin or Neuraminidase proteins. We aim to develop new therapeutic antiviral solutions to combat the disease. Beyond state of the art: The project combines knowledge based design and synthesis of compounds with unique patented image analysis and mathematical algorithm software to find and develop new types of potential antiviral molecules. The expertise and methodology allows for rapid discovery of lead molecules with the potential to provide new classes of drugs/vaccines which are less sensitive to viral mutation or reassortment. Work plan: Key molecules with optimal binding kinetics to the Influenza capsid protein will be designed and synthesized then analysed and tested in two separate experimental systems for their effect upon the virus structure and maturation process. The evaluation of novel lead drugs will be performed using a combination of new rapid image analysis, backed up by established viral analysis techniques. Finally a plan will be created for the continued verification and development of the lead molecules. Impact: We aim to produce a new class of antiviral drug candidates which specifically bind to influenza A capsid protein. These substances may have two potential effects; 1. Binding could inhibit important protein-protein interactions thereby inhibit virus formation. 2. Binding to the capsid protein could change the virus structure or stabilize the virus particle, resulting in non-infectious particles to which the hosts immune system could respond. The expected impact will be i) identification of targets against influenza to provide new therapeutic options ii) new opportunities to develop an anti-influenza vaccine which might help prevent an influenza pandemic, iii) to support the continued commercial development of the two SME partners.


Grant
Agency: Cordis | Branch: FP7 | Program: CP-IP | Phase: HEALTH-2007-2.1.1-5 | Award Amount: 14.64M | Year: 2008

Cys-loop receptors (CLRs) form a superfamily of structurally related neurotransmitter-gated ion channels, comprising nicotinic acetylcholine, glycine, GABA-A/C and serotonin (5HT3) receptors, crucial to function of the peripheral and central nervous system. CLRs cover a wide spectrum of functions, ranging from muscle contraction to cognitive functions. CLR (mal)function is linked to various disorders, including muscular dystrophies, neurodegenerative diseases, e.g. Alzheimers and Parkinsons, and neuropsychiatric diseases, e.g. schizophrenia, epilepsy and addiction. CLRs are potentially important drug targets for treatment of disease. However, novel drug discovery strategies call for in depth understanding of ligand binding sites, the structure-function relationships of these receptors and insight into their actions in the nervous system. NeuroCypres assembles the expertise of leading European laboratories to provide a technology workflow, which enables to embark on this next step in CLR structure and function. A major target of this project is to obtain high-resolution X-ray and NMR structures for CLRs and their complexes with diverse ligands, agonists/antagonists, channel blockers and modulators, which will reveal basic mechanisms of receptor functioning from ligand binding to gating and open new avenues to rational drug design. In addition, the project aims at understanding receptor function in the context of the brain, focusing on receptor biosensors, receptor-protein interactions and transgenic models. This major challenge requires application and development of a multidisciplinary workflow of high-throughput (HT) crystallization and HT-electrophysiology technologies, X-ray analysis, NMR and computational modeling, fragment-based drug design, innovative quantitative methods of interaction-proteomics, sensitive methods for visualization of activity and localization of receptors and studies of in vitro and in vivo function in animal models of disease.


Grant
Agency: Cordis | Branch: H2020 | Program: MSCA-ITN-ETN | Phase: MSCA-ITN-2015-ETN | Award Amount: 3.84M | Year: 2016

The promise of more efficient lead discovery is fuelling the enthusiasm for fragment-based lead discovery (FBLD). In this approach, highly sensitive biochemical and biophysical screening technologies are being used to detect the low affinity binding of low molecular weight compounds (the so-called fragments) to protein targets that are involved in pathophysiological processes. By investigating the molecular interactions between fragment hit(s) and the target protein, a detailed understanding of the binding event is obtained. This enables the rational and efficient optimisation of the hit fragment. The optimised compounds represent high quality leads for drug development. The necessary FBLD technologies and approaches have emerged mainly from small and specialised biotech companies. At present, FBLD is being adopted throughout pharmaceutical sciences, including by pharmaceutical companies, SMEs and academic research groups. So far, the necessary training that is needed to obtain an holistic view of the possibilities and opportunities that FBLD provides is missing, most likely because the highly multidisciplinary nature of the FBLD work is difficult to capture within one (academic) institute. Therefore, we have established FragNet as a dedicated FBLD training network. The consortium consists of the most prominent pharmaceutical companies, biotech companies and academic groups that have jointly shaped the FBLD research area. FragNet is committed to train 15 ESRs in all facets of FBLD using the combined technologies, skills and knowledge. This will include both research (e.g., technologies on the interface of chemistry and biology) and transferable skill sets (e.g., writing, media training, entrepreneurship and thorough understanding of scientific knowledge transfer). This will enable the ESRs to excel in todays drug discovery and chemical biology programmes that are performed in public and private organisations in the pharmaceutical sciences.

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