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.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Jul 01, 2017
- Source ID
- 10.1128/jvi.02418-16
Entities
People
- Binhua Ling
- Cary Retterer
- Chul Min Park
- Deemah Dabbagh
- Dima Gharaibeh
- Fei Yi
- Ha Jeung Park
- Hong Shang
- Jacque Fontenot
- Jia Guo
- John A. T. Young
- John Naughton
- Ke Zheng
- Kylene Kehn-Hall
- Margaret L. Pitt
- Mark Spear
- Mathieu Bibian
- Ramin M Hakami
- Rouzbeh Zamani
- Sijia He
- Sina Bavari
- Veronica Soloveva
- Xuehua Xu
- Yangbo Feng
- Yin Yan
- Yongjun Jiang
- Yuntao Wu
Organizations
- Defense Threat Reduction Agency
- George Mason University
- Henry M. Jackson Foundation for the Advancement of Military Medicine
- National Institute of Allergy and Infectious Diseases
- Translational Research Institute
- Tulane National Primate Research Center
- United States Army Medical Research Institute of Infectious Diseases
- United States Department of Health and Human Services