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Antimicrobial Agents and Chemotherapy, September 2005, p. 3755-3761, Vol. 49, No. 9
0066-4804/05/$08.00+0     doi:10.1128/AAC.49.9.3755-3761.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Design of a Small-Molecule Entry Inhibitor with Activity against Primary Measles Virus Strains

Richard K. Plemper,1* Joshua Doyle,1 Aiming Sun,2 Andrew Prussia,2 Li-Ting Cheng,1 Paul A. Rota,3 Dennis C. Liotta,2 James P. Snyder,2 and Richard W. Compans1

Department of Microbiology and Immunology, 3086 Rollins Research Center, 1510 Clifton Road, Emory University School of Medicine, Atlanta, Georgia 30322,1 Department of Chemistry, 1515 Pierce Drive, Emory University, Atlanta, Georgia 30322,2 Measles Virus Section, National Center for Infectious Diseases, Centers for Disease Control and Prevention, 1600 Clifton Road, MS-C22, Atlanta, Georgia 303333

Received 20 May 2005/ Returned for modification 15 June 2005/ Accepted 5 July 2005

The incidence of measles virus (MV) infection has been significantly reduced in many nations through extensive vaccination; however, the virus still causes significant morbidity and mortality in developing countries. Measles outbreaks also occur in some developed countries that have failed to maintain high vaccine coverage rates. While vaccination is essential in preventing the spread of measles, case management would greatly benefit from the use of therapeutic agents to lower morbidity. Thus, the development of new therapeutic strategies is desirable. We previously reported the generation of a panel of small-molecule MV entry inhibitors. Here we show that our initial lead compound, although providing proof of concept for our approach, has a short half-life (<16 h) under physiological conditions. In order to combine potent antiviral activity with increased compound stability, a targeted library of candidate molecules designed on the structural basis of the first lead has been synthesized and tested against MV. We have identified an improved lead with low toxicity and high stability (half-life >> 16 h) that prevents viral entry and hence infection. This compound shows high MV specificity and strong activity (50% inhibitory concentration = 0.6 to 3.0 µM, depending on the MV genotype) against a panel of wild-type MV strains representative of viruses that are currently endemic in the field.

* Corresponding author. Mailing address: Department of Microbiology and Immunology, 3086 Rollins Research Center, 1510 Clifton Road, Emory University School of Medicine, Atlanta, GA 30322. Phone: (404) 727-3228. Fax: (404) 727-5280. E-mail: rplempe{at}emory.edu.

Antimicrobial Agents and Chemotherapy, September 2005, p. 3755-3761, Vol. 49, No. 9
0066-4804/05/$08.00+0     doi:10.1128/AAC.49.9.3755-3761.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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