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PEDS Advance Access originally published online on June 8, 2004
Protein Engineering Design and Selection 2004 17(4):391-397; doi:10.1093/protein/gzh043
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Protein Engineering, Design & Selection vol. 17 no. 4 © Oxford University Press 2004; all rights reserved

Finding a new vaccine in the ricin protein fold

Mark A. Olson, John H. Carra, Virginia Roxas-Duncan, Robert W. Wannemacher, Leonard A. Smith and Charles B. Millard1

United States Army Medical Research Institute of Infectious Diseases, 1425 Porter Street, Fort Detrick, MD 21702-5011, USA

1 To whom correspondence should be addressed. E-mail: charles.b.millard{at}us.army.mil

Previous attempts to produce a vaccine for ricin toxin have been hampered by safety concerns arising from residual toxicity and the undesirable aggregation or precipitation caused by exposure of hydrophobic surfaces on the ricin A-chain (RTA) in the absence of its natural B-chain partner. We undertook a structure-based solution to this problem by reversing evolutionary selection on the ‘ribosome inactivating protein’ fold of RTA to arrive at a non-functional, compacted single-domain scaffold (sequence RTA1–198) for presentation of a specific protective epitope (RTA loop 95–110). An optimized protein based upon our modeling design (RTA1–33/44–198) showed greater resistance to thermal denaturation, less precipitation under physiological conditions and a reduction in toxic activity of at least three orders of magnitude compared with RTA. Most importantly, RTA1–198 or RTA1–33/44–198 protected 100% of vaccinated animals against supra-lethal challenge with aerosolized ricin. We conclude that comparative protein analysis and engineering yielded a superior vaccine by exploiting a component of the toxin that is inherently more stable than is the parent RTA molecule.

Received May 3, 2004; accepted May 10, 2004.

Edited by Amnon Horovitz


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