title: Discovery of Novel Small-Molecule Inhibitors of LIM Domain Kinase for Inhibiting HIV-1.
abstract: A dynamic actin cytoskeleton is necessary for viral entry, intracellular migration, and virion release. For HIV-1 infection, during entry, the virus triggers early actin activity by hijacking chemokine coreceptor signaling, which activates a host dependency factor, cofilin, and its kinase, the LIM domain kinase (LIMK). Although knockdown of human LIM domain kinase 1 (LIMK1) with short hairpin RNA (shRNA) inhibits HIV infection, no specific small-molecule inhibitor of LIMK has been available. Here, we describe the design and discovery of novel classes of small-molecule inhibitors of LIMK for inhibiting HIV infection. We identified R10015 as a lead compound that blocks LIMK activity by binding to the ATP-binding pocket. R10015 specifically blocks viral DNA synthesis, nuclear migration, and virion release. In addition, R10015 inhibits multiple viruses, including Zaire ebolavirus (EBOV), Rift Valley fever virus (RVFV), Venezuelan equine encephalitis virus (VEEV), and herpes simplex virus 1 (HSV-1), suggesting that LIMK inhibitors could be developed as a new class of broad-spectrum antiviral drugs.IMPORTANCEThe actin cytoskeleton is a structure that gives the cell shape and the ability to migrate. Viruses frequently rely on actin dynamics for entry and intracellular migration. In cells, actin dynamics are regulated by kinases, such as the LIM domain kinase (LIMK), which regulates actin activity through phosphorylation of cofilin, an actin-depolymerizing factor. Recent studies have found that LIMK/cofilin are targeted by viruses such as HIV-1 for propelling viral intracellular migration. Although inhibiting LIMK1 expression blocks HIV-1 infection, no highly specific LIMK inhibitor is available. This study describes the design, medicinal synthesis, and discovery of small-molecule LIMK inhibitors for blocking HIV-1 and several other viruses and emphasizes the feasibility of developing LIMK inhibitors as broad-spectrum antiviral drugs.
authors.affiliation: National Center for Biodefense and Infectious Diseases, George Mason University, Manassas, Virginia, USA.
authors.forename: Fei
authors.initials: F
authors.lastname: Yi
authors.affiliation: National Center for Biodefense and Infectious Diseases, George Mason University, Manassas, Virginia, USA.
authors.forename: Jia
authors.initials: J
authors.lastname: Guo
authors.affiliation: National Center for Biodefense and Infectious Diseases, George Mason University, Manassas, Virginia, USA.
authors.forename: Deemah
authors.initials: D
authors.lastname: Dabbagh
authors.affiliation: National Center for Biodefense and Infectious Diseases, George Mason University, Manassas, Virginia, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Spear
authors.affiliation: Department of Laboratory Medicine, China Medical University, Shenyang, China.
authors.forename: Sijia
authors.initials: S
authors.lastname: He
authors.affiliation: National Center for Biodefense and Infectious Diseases, George Mason University, Manassas, Virginia, USA.
authors.forename: Kylene
authors.initials: K
authors.lastname: Kehn-Hall
authors.affiliation: National Center for Biodefense and Infectious Diseases, George Mason University, Manassas, Virginia, USA.
authors.forename: Jacque
authors.initials: J
authors.lastname: Fontenot
authors.affiliation: Medicinal Chemistry, Translational Research Institute, The Scripps Research Institute, Jupiter, Florida, USA.
authors.forename: Yan
authors.initials: Y
authors.lastname: Yin
authors.affiliation: Medicinal Chemistry, Translational Research Institute, The Scripps Research Institute, Jupiter, Florida, USA.
authors.forename: Mathieu
authors.initials: M
authors.lastname: Bibian
authors.affiliation: Medicinal Chemistry, Translational Research Institute, The Scripps Research Institute, Jupiter, Florida, USA.
authors.forename: Chul Min
authors.initials: CM
authors.lastname: Park
authors.affiliation: Medicinal Chemistry, Translational Research Institute, The Scripps Research Institute, Jupiter, Florida, USA.
authors.forename: Ke
authors.initials: K
authors.lastname: Zheng
authors.affiliation: Medicinal Chemistry, Translational Research Institute, The Scripps Research Institute, Jupiter, Florida, USA.
authors.forename: Ha Jeung
authors.initials: HJ
authors.lastname: Park
authors.affiliation: U.S. Army Medical Research Institute of Infectious Diseases, Frederick, Maryland, USA.|Henry M. Jackson Foundation, Bethesda, Maryland, USA.
authors.forename: Veronica
authors.initials: V
authors.lastname: Soloveva
authors.affiliation: U.S. Army Medical Research Institute of Infectious Diseases, Frederick, Maryland, USA.
authors.forename: Dima
authors.initials: D
authors.lastname: Gharaibeh
authors.affiliation: U.S. Army Medical Research Institute of Infectious Diseases, Frederick, Maryland, USA.
authors.forename: Cary
authors.initials: C
authors.lastname: Retterer
authors.affiliation: U.S. Army Medical Research Institute of Infectious Diseases, Frederick, Maryland, USA.
authors.forename: Rouzbeh
authors.initials: R
authors.lastname: Zamani
authors.affiliation: U.S. Army Medical Research Institute of Infectious Diseases, Frederick, Maryland, USA.
authors.forename: Margaret L
authors.initials: ML
authors.lastname: Pitt
authors.affiliation: Nomis Foundation Laboratories for Immunobiology and Microbial Pathogenesis, Salk Institute of Biological Studies, La Jolla, California, USA.
authors.forename: John
authors.initials: J
authors.lastname: Naughton
authors.affiliation: Department of Laboratory Medicine, China Medical University, Shenyang, China.
authors.forename: Yongjun
authors.initials: Y
authors.lastname: Jiang
authors.affiliation: Department of Laboratory Medicine, China Medical University, Shenyang, China.
authors.forename: Hong
authors.initials: H
authors.lastname: Shang
authors.affiliation: National Center for Biodefense and Infectious Diseases, George Mason University, Manassas, Virginia, USA.
authors.forename: Ramin M
authors.initials: RM
authors.lastname: Hakami
authors.affiliation: Tulane National Primate Research Center, Covington, Louisiana, USA.
authors.forename: Binhua
authors.initials: B
authors.lastname: Ling
authors.affiliation: Nomis Foundation Laboratories for Immunobiology and Microbial Pathogenesis, Salk Institute of Biological Studies, La Jolla, California, USA.
authors.forename: John A T
authors.initials: JAT
authors.lastname: Young
authors.affiliation: U.S. Army Medical Research Institute of Infectious Diseases, Frederick, Maryland, USA.
authors.forename: Sina
authors.initials: S
authors.lastname: Bavari
authors.affiliation: Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, Rockville, Maryland, USA.
authors.forename: Xuehua
authors.initials: X
authors.lastname: Xu
authors.affiliation: Reaction Biology Corporation, Malvern, Pennsylvania, USA yangbof@gmail.com ywu8@gmu.edu.
authors.forename: Yangbo
authors.initials: Y
authors.lastname: Feng
authors.affiliation: National Center for Biodefense and Infectious Diseases, George Mason University, Manassas, Virginia, USA yangbof@gmail.com ywu8@gmu.edu.
authors.forename: Yuntao
authors.identifier: http://orcid.org/0000-0002-9547-3278
authors.initials: Y
authors.lastname: Wu
mesh_terms: D000998:Antiviral Agents / Q000138:chemical synthesis / Q000302:isolation & purification / Q000494:pharmacology*; D002478:Cells, Cultured; D029043:Ebolavirus / Q000187:drug effects; D004666:Encephalitis Virus, Venezuelan Equine / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000302:isolation & purification / Q000494:pharmacology*; D015497:HIV-1 / Q000187:drug effects* / Q000502:physiology; D018259:Herpesvirus 1, Human / Q000187:drug effects; D006801:Humans; D054461:Lim Kinases / Q000037:antagonists & inhibitors*; D008826:Microbial Sensitivity Tests; D062105:Molecular Docking Simulation; D012296:Rift Valley fever virus / Q000187:drug effects; D057074:Virus Release / Q000187:drug effects*; D014779:Virus Replication / Q000187:drug effects*
chemical_list: D000998:Antiviral Agents; D004791:Enzyme Inhibitors; C515892:LIMK1 protein, human; D054461:Lim Kinases
keywords: CXCR4; Ebola virus; LIM domain kinase; Rift Valley fever virus; Venezuelan equine encephalitis virus; actin; cofilin; cytoskeleton; herpes simplex virus; human immunodeficiency virus