2. Academic Validation
  3. Synthesis and Structure-Activity Relationships of 3,5-Disubstituted-pyrrolo[2,3- b]pyridines as Inhibitors of Adaptor-Associated Kinase 1 with Antiviral Activity

Synthesis and Structure-Activity Relationships of 3,5-Disubstituted-pyrrolo[2,3- b]pyridines as Inhibitors of Adaptor-Associated Kinase 1 with Antiviral Activity

  • J Med Chem. 2019 Jun 27;62(12):5810-5831. doi: 10.1021/acs.jmedchem.9b00136.
Sven Verdonck 1,  Szu-Yuan Pu 2,  Fiona J Sorrell 3,  Jon M Elkins 3 4,  Mathy Froeyen 1,  Ling-Jie Gao 1,  Laura I Prugar 5,  Danielle E Dorosky 5,  Jennifer M Brannan 5,  Rina Barouch-Bentov 2,  Stefan Knapp 3 6,  John M Dye 5,  Piet Herdewijn 1,  Shirit Einav 2,  Steven De Jonghe 1
Affiliations

Affiliations

  • 1 Medicinal Chemistry, Rega Institute for Medical Research , KU Leuven , Herestraat 49-bus 1041 , 3000 Leuven , Belgium.
  • 2 Department of Medicine, Division of Infectious Diseases and Geographic Medicine, and Department of Microbiology and Immunology , Stanford University School of Medicine , Stanford , California 94305 , United States.
  • 3 Nuffield Department of Clinical Medicine, Target Discovery Institute (TDI) and Structural Genomics Consortium (SGC) , University of Oxford , Old Road Campus, Roosevelt Drive , Oxford OX3 7DQ , U.K.
  • 4 Structural Genomics Consortium , Universidade Estadual de Campinas , Cidade Universitária Zeferino Vaz, Av. Dr. André Tosello, 550 , Barão Geraldo, Campinas , São Paulo 13083-886 , Brazil.
  • 5 US Army Medical Research Institute of Infectious Diseases , Viral Immunology Branch , Fort Detrick , Maryland 21702 , United States.
  • 6 Institute for Pharmaceutical Chemistry, Buchmann Institute for Life Sciences Campus Riedbeerg , Goethe-University Frankfurt , 60438 Frankfurt am Main , Germany.
PMID: 31136173 DOI: 10.1021/acs.jmedchem.9b00136
Abstract

There are currently no approved drugs for the treatment of emerging viral infections, such as dengue and Ebola. Adaptor-associated kinase 1 (AAK1) is a cellular serine-threonine protein kinase that functions as a key regulator of the clathrin-associated host adaptor proteins and regulates the intracellular trafficking of multiple unrelated RNA viruses. Moreover, AAK1 is overexpressed specifically in dengue virus-infected but not bystander cells. Because AAK1 is a promising Antiviral drug target, we have embarked on an optimization campaign of a previously identified 7-azaindole analogue, yielding novel pyrrolo[2,3- b]pyridines with high AAK1 affinity. The optimized compounds demonstrate improved activity against dengue virus both in vitro and in human primary dendritic cells and the unrelated Ebola virus. These findings demonstrate that targeting cellular AAK1 may represent a promising broad-spectrum Antiviral strategy.

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