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Fragment-based drug design of antivirals targeting the polyomavirus capsid and flaviviral NS3-helicase KU Leuven

Sergei Strelkov
Biocrystallography

BK and JC viruses are closely related, non-enveloped, pathogenic DNA viruses of the polyomavirus family for which there are no approved treatments. These viruses cause latent infection in humans and have an extremely high prevalence worldwide (70-90% of the population is seropositive). However, clinical manifestation is seen only in immunocompromised patients which can lead to severe and often fatal complications. BK virus for instance, is a ...

Fragment-based computational design of inhibitors of dipeptidyl peptidase 8 and 9. University of Antwerp

Hans De Winter
Medicinal Chemistry (UAMC)
Evaluation of the binding affinity of small molecules against therapeutically relevant proteins is currently performed using in vitro assays tailored to the specific problem at hand. However, despite their proven usefulness, compound solubility issues and limited chemical diversity imposed by the input compound library, emphasise some drawbacks. Fragment-based methods have also been introduced in which fragments are linked up with other ...

Protein structures for health: Structural biology of therapeutic membrane proteins as a starting point for effective rational drug design. Vrije Universiteit Brussel

Université libre de Bruxelles, Department of Bio-engineering Sciences
Drugs targeting GPCRs accounted for over EURO60bn of the pharmaceutical industry's annual sales in 2009, about 25% of the worldwide pharmaceutical market in that year. Ion-channels and transporters represent the second largest class of drugable targets and it is expected that membrane proteins will continue to constitute the majority of drug targets in the future, because it is usually at the membrane level (receptors, channels, transporters) ...

Rational discovery of drug compounds targeting the chromatin-reading function of LEDGF/p75 towards the treatment for acute MLL-rearranged leukemia KU Leuven

Sergei Strelkov
Biocrystallography

Mixed-lineage leukemia rearranged (MLL-r) is an acute leukemia mostly affecting children and associated with poor survival. The disease is caused by rearrangements in the MLL gene resulting in malignant fusion proteins. LEDGF/p75 serves as an epigenetic reader and tethers transcription complexes containing MLL to chromatin via its PWWP domain. Recent studies demonstrated that this process is essential for the onset of MLL-r leukemia, yet it ...

Structure-guided design and development of antivirals targeting BK polyomavirus capsid KU Leuven

Sergei Strelkov
Biocrystallography, Laboratory of Virology and Chemotherapy (Rega Institute), Medicinal Chemistry (Rega Institute)
We aim to rationally devise first-in-class compounds active against polyomaviruses which are linked to several diseases including cancer. In particular, BK polyomavirus (BKPyV) latently infects 80% of humans. Its reactivation in immunocompromised patients such as those undergoing kidney transplantation leads to severe complications including graft loss and acute renal failure in 5-10% cases. No approved drugs to combat BKPyV are currently ...

Exploiting the methylerythritol phosphate pathway as a source of drug targets for novel anti-infectives Ghent University

Serge Van Calenbergh
Department of Pharmaceutics, Helmholtz Centre for Infection Research, Swiss Tropical and Public Health Institute, University of Groningen, Atomic Energy and Alternative Energies Commission, University of Bergen, University of Dundee, University of Strasbourg

Anti-infective resistance is a serious global healthcare issue, calling for the development of compounds with a novel mode of action. An interdisciplinary approach will afford potent and selective inhibitors of the underexplored methylerythritol phosphate pathway, a rich source of targets that are essential for medically relevant pathogens such as the causative agents of malaria and tuberculosis. The discovery of anti-infective agents ...

Structure-based design of inhibitors targeting the chromatin-reading function of LEDGF/p75 to treat acute mixed-lineage leukemia KU Leuven

Sergei Strelkov
Biocrystallography, Molecular Virology and Gene Therapy

Mixed-lineage leukemia rearranged (MLL-r) is an acute leukemia mostly affecting children and associated with poor survival. The disease is caused by rearrangements in the MLL gene resulting in malignant fusion proteins. LEDGF/p75 serves as an epigenetic reader and tethers transcription complexes containing MLL to chromatin via its PWWP domain. Recent studies demonstrated that this process is essential for the onset of MLL-r leukemia, yet it ...

Structure-guided design of BK/JC virus capsid targeting antivirals KU Leuven

Sergei Strelkov
Biocrystallography

BK and JC viruses are closely related members of the polyomavirus family that latently infect 70-90% of humans and cause fatal clinical complications in immunocompromised patients (kidney failure and brain demyelination). There are no effective drugs to treat these infections. The lack of conventional, enzymatic antiviral targets such as proteases or integrases makes any development challeging. The small genome of polyomaviruses encodes two ...

Rational Design of XNA Processing Enzymes KU Leuven

Eveline Lescrinier
Medicinal Chemistry (Rega Institute)

Xenobiotic Nucleic Acids (XNA) are synthetic analogues of natural nucleic acids (DNA and RNA). They are developed for applications such as therapeutics, diagnostics and alternative carriers of genetic information. The main goal of the PhD research is to develop a 'toolbox' with enzymes for XNA in molecular biology that is based on rational insights.

In chapter 2, currently available computer-driven algorithms were explored for their ...