Naegleria fowleri: Protein structures to facilitate drug discovery for the deadly, pathogenic free-living amoeba.

Autor: Tillery L; Department of Medicine, Division Allergy and Infectious Disease, Center for Emerging and Re-emerging Infectious Disease (CERID) University of Washington, Seattle, Washington, United States of America.; Seattle Structural Genomics Center for Infectious Diseases, Seattle, Washington, United States of America., Barrett K; Department of Medicine, Division Allergy and Infectious Disease, Center for Emerging and Re-emerging Infectious Disease (CERID) University of Washington, Seattle, Washington, United States of America.; Seattle Structural Genomics Center for Infectious Diseases, Seattle, Washington, United States of America., Goldstein J; Department of Biology, Washington University, St. Louis, Missouri, United States of America., Lassner JW; Department of Biology, Washington University, St. Louis, Missouri, United States of America., Osterhout B; Department of Biology, Washington University, St. Louis, Missouri, United States of America., Tran NL; Department of Biology, Washington University, St. Louis, Missouri, United States of America., Xu L; Department of Biology, Washington University, St. Louis, Missouri, United States of America., Young RM; Department of Biology, Washington University, St. Louis, Missouri, United States of America., Craig J; Department of Medicine, Division Allergy and Infectious Disease, Center for Emerging and Re-emerging Infectious Disease (CERID) University of Washington, Seattle, Washington, United States of America.; Seattle Structural Genomics Center for Infectious Diseases, Seattle, Washington, United States of America., Chun I; Department of Medicine, Division Allergy and Infectious Disease, Center for Emerging and Re-emerging Infectious Disease (CERID) University of Washington, Seattle, Washington, United States of America.; Seattle Structural Genomics Center for Infectious Diseases, Seattle, Washington, United States of America., Dranow DM; Seattle Structural Genomics Center for Infectious Diseases, Seattle, Washington, United States of America.; UCB Pharma, Bainbridge Island, Washington, United States of America., Abendroth J; Seattle Structural Genomics Center for Infectious Diseases, Seattle, Washington, United States of America.; UCB Pharma, Bainbridge Island, Washington, United States of America., Delker SL; Seattle Structural Genomics Center for Infectious Diseases, Seattle, Washington, United States of America.; UCB Pharma, Bainbridge Island, Washington, United States of America., Davies DR; Seattle Structural Genomics Center for Infectious Diseases, Seattle, Washington, United States of America.; UCB Pharma, Bainbridge Island, Washington, United States of America., Mayclin SJ; Seattle Structural Genomics Center for Infectious Diseases, Seattle, Washington, United States of America.; UCB Pharma, Bainbridge Island, Washington, United States of America., Calhoun B; Seattle Structural Genomics Center for Infectious Diseases, Seattle, Washington, United States of America.; UCB Pharma, Bainbridge Island, Washington, United States of America., Bolejack MJ; Seattle Structural Genomics Center for Infectious Diseases, Seattle, Washington, United States of America.; UCB Pharma, Bainbridge Island, Washington, United States of America., Staker B; Seattle Structural Genomics Center for Infectious Diseases, Seattle, Washington, United States of America.; Seattle Children's Research Institute, Seattle, Washington, United States of America., Subramanian S; Seattle Structural Genomics Center for Infectious Diseases, Seattle, Washington, United States of America.; Seattle Children's Research Institute, Seattle, Washington, United States of America., Phan I; Seattle Structural Genomics Center for Infectious Diseases, Seattle, Washington, United States of America.; Seattle Children's Research Institute, Seattle, Washington, United States of America., Lorimer DD; Seattle Structural Genomics Center for Infectious Diseases, Seattle, Washington, United States of America.; UCB Pharma, Bainbridge Island, Washington, United States of America., Myler PJ; Seattle Structural Genomics Center for Infectious Diseases, Seattle, Washington, United States of America.; Seattle Children's Research Institute, Seattle, Washington, United States of America.; Department of Pediatrics, University of Washington, Seattle, Washington, United States of America.; Department of Biomedical Informatics & Medical Education, University of Washington, Seattle, Washington, United States of America.; Department of Global Health (Pathobiology), University of Washington, Seattle, Washington, United States of America., Edwards TE; Seattle Structural Genomics Center for Infectious Diseases, Seattle, Washington, United States of America.; UCB Pharma, Bainbridge Island, Washington, United States of America., Kyle DE; Center for Tropical and Emerging Global Diseases, University of Georgia, Athens, Georgia, United States of America., Rice CA; Center for Tropical and Emerging Global Diseases, University of Georgia, Athens, Georgia, United States of America., Morris JC; Eukaryotic Pathogens Innovation Center, Department of Genetics and Biochemistry, Clemson University, Clemson, South Carolina, United States of America., Leahy JW; Department of Chemistry, University of South Florida, Tampa, Florida, United States of America., Manetsch R; Department of Chemistry and Chemical Biology and Department of Pharmaceutical Sciences, Northeastern University, Boston, Massachusetts, United States of America., Barrett LK; Department of Medicine, Division Allergy and Infectious Disease, Center for Emerging and Re-emerging Infectious Disease (CERID) University of Washington, Seattle, Washington, United States of America.; Seattle Structural Genomics Center for Infectious Diseases, Seattle, Washington, United States of America., Smith CL; Department of Biology, Washington University, St. Louis, Missouri, United States of America., Van Voorhis WC; Department of Medicine, Division Allergy and Infectious Disease, Center for Emerging and Re-emerging Infectious Disease (CERID) University of Washington, Seattle, Washington, United States of America.; Seattle Structural Genomics Center for Infectious Diseases, Seattle, Washington, United States of America.; Department of Global Health (Pathobiology), University of Washington, Seattle, Washington, United States of America.
Jazyk: angličtina
Zdroj: PloS one [PLoS One] 2021 Mar 24; Vol. 16 (3), pp. e0241738. Date of Electronic Publication: 2021 Mar 24 (Print Publication: 2021).
DOI: 10.1371/journal.pone.0241738
Abstrakt: Naegleria fowleri is a pathogenic, thermophilic, free-living amoeba which causes primary amebic meningoencephalitis (PAM). Penetrating the olfactory mucosa, the brain-eating amoeba travels along the olfactory nerves, burrowing through the cribriform plate to its destination: the brain's frontal lobes. The amoeba thrives in warm, freshwater environments, with peak infection rates in the summer months and has a mortality rate of approximately 97%. A major contributor to the pathogen's high mortality is the lack of sensitivity of N. fowleri to current drug therapies, even in the face of combination-drug therapy. To enable rational drug discovery and design efforts we have pursued protein production and crystallography-based structure determination efforts for likely drug targets from N. fowleri. The genes were selected if they had homology to drug targets listed in Drug Bank or were nominated by primary investigators engaged in N. fowleri research. In 2017, 178 N. fowleri protein targets were queued to the Seattle Structural Genomics Center of Infectious Disease (SSGCID) pipeline, and to date 89 soluble recombinant proteins and 19 unique target structures have been produced. Many of the new protein structures are potential drug targets and contain structural differences compared to their human homologs, which could allow for the development of pathogen-specific inhibitors. Five of the structures were analyzed in more detail, and four of five show promise that selective inhibitors of the active site could be found. The 19 solved crystal structures build a foundation for future work in combating this devastating disease by encouraging further investigation to stimulate drug discovery for this neglected pathogen.
Competing Interests: The authors have read the journal’s policy and have the following competing interests: DMD, JA, SLD, DRD, SJM, BC, MJB, DDL, and TEE are employees of UCB Pharma. The LS-CAT Sector 21 was supported by a grant from the Michigan Economic Development Corporation. This does not alter our adherence to PLOS ONE policies on sharing data and materials. There are no patents, products in development or marketed products associated with this research to declare.
Databáze: MEDLINE
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