期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 62, 期 12, 页码 5810-5831出版社
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.9b00136
关键词
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资金
- Department of Defense (DoD), Congressionally Directed Medical Research Programs (CDMRP) [W81XWH-16-1-0691]
- Defense Threat Reduction Agency (DTRA), Fundamental Research to Counter Weapons of Mass Destruction [12393481]
- Stanford SPARK program
- Research Foundation-Flanders [1S00116N]
- Child Health Research Institute
- Lucile Packard Foundation for Children's Health
- Stanford CSTA [UL1 TR000093]
- AbbVie [1097737]
- Bayer Pharma AG [1097737]
- Boehringer Ingelheim [1097737]
- Canada Foundation for Innovation [1097737]
- Eshelman Institute for Innovation [1097737]
- Genome Canada [1097737]
- Innovative Medicines Initiative (EU/EFPIA) [ULTRA-DD grant] [1097737, 115766]
- Janssen [1097737]
- Merck KGaA Darmstadt Germany [1097737]
- MSD [1097737]
- Novartis Pharma AG [1097737]
- Ontario Ministry of Economic Development and Innovation [1097737]
- Pfizer [1097737]
- sao Paulo Research Foundation-FAPESP [1097737]
- Takeda [1097737]
- Wellcome [1097737, 106169/ZZ14/Z]
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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