دورية أكاديمية
Shotgun Kinetic Target-Guided Synthesis Approach Enables the Discovery of Small-Molecule Inhibitors against Pathogenic Free-Living Amoeba Glucokinases.
العنوان: | Shotgun Kinetic Target-Guided Synthesis Approach Enables the Discovery of Small-Molecule Inhibitors against Pathogenic Free-Living Amoeba Glucokinases. |
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المؤلفون: | Kassu M; Department of Chemistry and Chemical Biology, Northeastern University, Boston, Massachusetts 02115, United States., Parvatkar PT; Department of Chemistry and Chemical Biology, Northeastern University, Boston, Massachusetts 02115, United States., Milanes J; Eukaryotic Pathogens Innovation Center, Department of Genetics and Biochemistry, Clemson University, Clemson, South Carolina 29634, United States., Monaghan NP; Eukaryotic Pathogens Innovation Center, Department of Genetics and Biochemistry, Clemson University, Clemson, South Carolina 29634, United States., Kim C; Department of Chemistry and Chemical Biology, Northeastern University, Boston, Massachusetts 02115, United States., Dowgiallo M; Department of Chemistry and Chemical Biology, Northeastern University, Boston, Massachusetts 02115, United States., Zhao Y; Department of Chemistry and Chemical Biology, Northeastern University, Boston, Massachusetts 02115, United States., Asakawa AH; Department of Pharmaceutical Sciences, Northeastern University, Boston, Massachusetts 02115, United States., Huang L; Department of Chemistry and Chemical Biology, Northeastern University, Boston, Massachusetts 02115, United States., Wagner A; Department of Chemistry and Chemical Biology, Northeastern University, Boston, Massachusetts 02115, United States., Miller B; Department of Chemistry and Chemical Biology, Northeastern University, Boston, Massachusetts 02115, United States., Carter K; Department of Chemistry and Chemical Biology, Northeastern University, Boston, Massachusetts 02115, United States., Barrett KF; Center for Emerging and Re-emerging Infectious Diseases (CERID), Division of Allergy and Infectious Diseases, Department of Medicine, University of Washington School of Medicine, Seattle, Washington 98109, United States., Tillery LM; Center for Emerging and Re-emerging Infectious Diseases (CERID), Division of Allergy and Infectious Diseases, Department of Medicine, University of Washington School of Medicine, Seattle, Washington 98109, United States., Barrett LK; Center for Emerging and Re-emerging Infectious Diseases (CERID), Division of Allergy and Infectious Diseases, Department of Medicine, University of Washington School of Medicine, Seattle, Washington 98109, United States., Phan IQ; Center for Global Infectious Diseases Research, Seattle Children's Research Center, Seattle, Washington 98109, United States., Subramanian S; Center for Global Infectious Diseases Research, Seattle Children's Research Center, Seattle, Washington 98109, United States., Myler PJ; Center for Global Infectious Diseases Research, Seattle Children's Research Center, Seattle, Washington 98109, United States., Van Voorhis WC; Center for Emerging and Re-emerging Infectious Diseases (CERID), Division of Allergy and Infectious Diseases, Department of Medicine, University of Washington School of Medicine, Seattle, Washington 98109, United States., Leahy JW; Department of Chemistry, University of South Florida, Tampa, Florida 33620, United States., Rice CA; Department of Comparative Pathobiology, College of Veterinary Medicine, Purdue University, West Lafayette, Indiana 47907, United States.; Purdue Institute for Drug Discovery (PIDD), Purdue University, West Lafayette, Indiana 47907, United States.; Purdue Institute of Inflammation, Immunology and Infectious Disease (PI4D), Purdue University, West Lafayette, Indiana 47907, United States.; Department of Cellular Biology, University of Georgia, Athens, Georgia 30602, United States., Kyle DE; Department of Cellular Biology, University of Georgia, Athens, Georgia 30602, United States., Morris J; Eukaryotic Pathogens Innovation Center, Department of Genetics and Biochemistry, Clemson University, Clemson, South Carolina 29634, United States., Manetsch R; Department of Chemistry and Chemical Biology, Northeastern University, Boston, Massachusetts 02115, United States.; Department of Pharmaceutical Sciences, Northeastern University, Boston, Massachusetts 02115, United States.; Center for Drug Discovery, Northeastern University, Boston, Massachusetts 02115, United States.; Barnett Institute of Chemical and Biological Analysis, Northeastern University, Boston, Massachusetts 02115, United States. |
المصدر: | ACS infectious diseases [ACS Infect Dis] 2023 Nov 10; Vol. 9 (11), pp. 2190-2201. Date of Electronic Publication: 2023 Oct 11. |
نوع المنشور: | Journal Article; Research Support, N.I.H., Extramural |
اللغة: | English |
بيانات الدورية: | Publisher: ACS Publications Country of Publication: United States NLM ID: 101654580 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 2373-8227 (Electronic) Linking ISSN: 23738227 NLM ISO Abbreviation: ACS Infect Dis Subsets: MEDLINE |
أسماء مطبوعة: | Original Publication: Washington, DC : ACS Publications, [2015]- |
مواضيع طبية MeSH: | Amoeba* , Naegleria fowleri* , Balamuthia mandrillaris* , Acanthamoeba castellanii*, Humans ; Glucokinase |
مستخلص: | Pathogenic free-living amoebae (pFLA) can cause life-threatening central nervous system (CNS) infections and warrant the investigation of new chemical agents to combat the rise of infection from these pathogens. Naegleria fowleri glucokinase ( Nf Glck), a key metabolic enzyme involved in generating glucose-6-phosphate, was previously identified as a potential target due to its limited sequence similarity with human Glck ( Hs Glck). Herein, we used our previously demonstrated multifragment kinetic target-guided synthesis (KTGS) screening strategy to identify inhibitors against pFLA glucokinases. Unlike the majority of previous KTGS reports, our current study implements a "shotgun" approach, where fragments were not biased by predetermined binding potentials. The study resulted in the identification of 12 inhibitors against 3 pFLA glucokinase enzymes─ Nf Glck, Balamuthia mandrillaris Glck ( Bm Glck), and Acanthamoeba castellanii Glck ( Ac Glck). This work demonstrates the utility of KTGS to identify small-molecule binders for biological targets where resolved X-ray crystal structures are not readily accessible. |
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معلومات مُعتمدة: | 75N93022C00036 United States AI NIAID NIH HHS |
فهرسة مساهمة: | Keywords: glucokinases; kinetic target-guided synthesis; multifragment screening; small molecule inhibitors; sulfo-click reaction |
المشرفين على المادة: | EC 2.7.1.2 (Glucokinase) |
تواريخ الأحداث: | Date Created: 20231011 Date Completed: 20231113 Latest Revision: 20240210 |
رمز التحديث: | 20240210 |
مُعرف محوري في PubMed: | PMC10644346 |
DOI: | 10.1021/acsinfecdis.3c00284 |
PMID: | 37820055 |
قاعدة البيانات: | MEDLINE |
تدمد: | 2373-8227 |
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DOI: | 10.1021/acsinfecdis.3c00284 |