Structure Based Drug Discovery Targeting Helicobacter Pylori, Using Cryo-EM
Eva Cunha, Centre for Molecular Medicine Norway - University of Oslo
Host: Maria João Romão, UCIBIO-FCT NOVA
ZOOM link: https://bit.ly/GuestSeminarsUCIBIO
ID da reunião: 865 7786 0516
Abstract: Infection of the human stomach by Helicobacter pylori remains a worldwide problem and greatly contributes to peptic ulcer disease and gastric cancer. Without active intervention approximately 50% of the world population will continue to be infected with this gastric pathogen. Current eradication, called triple therapy, entails a proton-pump inhibitor and two broadband antibiotics, however resistance to either clarithromycin or metronidazole is greater than 25% and rising. Therefore, there is an urgent need for a targeted, high-specificity eradication drug. Gastric infection by H. pylori depends on the expression of a nickel-dependent urease in the cytoplasm of the bacteria. We have solved a 2.0 Å resolution structure of the 1.1 MDa urease in complex with an inhibitor by cryo-electron microscopy and compare it to a β-mercaptoethanol-inhibited structure at 2.5 Å resolution. We also present a new cryo-EM map at 1.68 Å resolution with a novel inhibitor bound. The structural information is of sufficient detail to aid in the development of inhibitors with high specificity and affinity.
Biosketch: Currently, I am a researcher and project leader in the Structural Biology and Drug Discovery (Luecke) Group at the Norwegian Center for Molecular Medicine (NCMM) in Oslo. I joined NCMM as a researcher in 2018, where I helped to establish single particle Cryo-EM in Oslo to better understand mechanistic details of membrane protein transport and of drugs with their respective targets. I was initially funded by a Marie Curie Individual Fellowship and have recently been awarded the Young Talent Grant by the Research Council of Norway. Previously, as a PhD candidate at Johns Hopkins University, Baltimore, USA, I used biophysics and thermodynamics in a project related to environmental sustainability, funded initially by a Fulbright/FLAD fellowship and later by a Foundation for Science and Technology PhD fellowship. I then worked as a postdoctoral researcher, first at CIC bioGUNE in Bilbao, Spain and later at the Max Planck Institute for Biophysics in Frankfurt, Germany. During both postdoctoral studies, I used structural biology and biophysics techniques in projects involving human health. Over the last few years, remarkable progress has been achieved in the field of Cryo-EM, resulting in structure determination at near-atomic resolution. I therefore believe that now is the perfect time to invest into and develop the field of Cryo-EM targeting important scientific problems that affect society at large.