title: Identification of agents effective against multiple toxins and viruses by host-oriented cell targeting.
abstract: A longstanding and still-increasing threat to the effective treatment of infectious diseases is resistance to antimicrobial countermeasures. Potentially, the targeting of host proteins and pathways essential for the detrimental effects of pathogens offers an approach that may discover broad-spectrum anti-pathogen countermeasures and circumvent the effects of pathogen mutations leading to resistance. Here we report implementation of a strategy for discovering broad-spectrum host-oriented therapies against multiple pathogenic agents by multiplex screening of drugs for protection against the detrimental effects of multiple pathogens, identification of host cell pathways inhibited by the drug, and screening for effects of the agent on other pathogens exploiting the same pathway. We show that a clinically used antimalarial drug, Amodiaquine, discovered by this strategy, protects host cells against infection by multiple toxins and viruses by inhibiting host cathepsin B. Our results reveal the practicality of discovering broadly acting anti-pathogen countermeasures that target host proteins exploited by pathogens.
authors: Keck Graduate Institute, Claremont, CA 91711.
authors: Leeor
authors: L
authors: Zilbermintz
authors: Keck Graduate Institute, Claremont, CA 91711.
authors: William
authors: W
authors: Leonardi
authors: Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305.
authors: Sun-Young
authors: SY
authors: Jeong
authors: Department of Chemistry and Biochemistry, University of California, Los Angeles, CA, 90095.
authors: Megan
authors: M
authors: Sjodt
authors: Keck Graduate Institute, Claremont, CA 91711.
authors: Ryan
authors: R
authors: McComb
authors: Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, CA, 90095.
authors: Chi-Lee C
authors: CL
authors: Ho
authors: US Army Medical Research Institute of Infectious Diseases (USAMRIID), Fort Detrick, MD, 21702.
authors: Cary
authors: C
authors: Retterer
authors: US Army Medical Research Institute of Infectious Diseases (USAMRIID), Fort Detrick, MD, 21702.
authors: Dima
authors: D
authors: Gharaibeh
authors: US Army Medical Research Institute of Infectious Diseases (USAMRIID), Fort Detrick, MD, 21702.
authors: Rouzbeh
authors: R
authors: Zamani
authors: US Army Medical Research Institute of Infectious Diseases (USAMRIID), Fort Detrick, MD, 21702.
authors: Veronica
authors: V
authors: Soloveva
authors: US Army Medical Research Institute of Infectious Diseases (USAMRIID), Fort Detrick, MD, 21702.
authors: Sina
authors: S
authors: Bavari
authors: Keck Graduate Institute, Claremont, CA 91711.
authors: Anastasia
authors: A
authors: Levitin
authors: Keck Graduate Institute, Claremont, CA 91711.
authors: Joel
authors: J
authors: West
authors: Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, CA, 90095.
authors: Kenneth A
authors: KA
authors: Bradley
authors: Department of Chemistry and Biochemistry, University of California, Los Angeles, CA, 90095.
authors: Robert T
authors: RT
authors: Clubb
authors: Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305.
authors: Stanley N
authors: SN
authors: Cohen
authors: Keck Graduate Institute, Claremont, CA 91711.
authors: Vivek
authors: V
authors: Gupta
authors: Keck Graduate Institute, Claremont, CA 91711.
authors: Mikhail
authors: M
authors: Martchenko
mesh_terms: D000655:Amodiaquine / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D000942:Antigens, Bacterial / Q000494:pharmacology*; D001427:Bacterial Toxins / Q000494:pharmacology*; D002401:Cathepsin B / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D003600:Cytosol / Q000187:drug effects / Q000378:metabolism; D017277:Drug Approval; D029043:Ebolavirus / Q000187:drug effects; D011992:Endosomes / Q000187:drug effects / Q000378:metabolism; D006367:HeLa Cells; D054884:Host-Pathogen Interactions / Q000187:drug effects*; D006801:Humans; D055442:Metabolome / Q000187:drug effects; D051379:Mice; D008954:Models, Biological; D000067996:RAW 264.7 Cells; D014481:United States; D014486:United States Food and Drug Administration; D014780:Viruses / Q000187:drug effects*
chemical_list: D000942:Antigens, Bacterial; D001427:Bacterial Toxins; C030325:anthrax toxin; D000655:Amodiaquine; D002401:Cathepsin B