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PEDS Advance Access published online on June 8, 2004
Protein Engineering Design and Selection, doi:10.1093/protein/gzh043
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Received May 3, 2004
Accepted May 10, 2004

Article

Finding a new vaccine in the ricin protein fold

Mark A. Olson 1, John H. Carra 1, Virginia Roxas-Duncan 1, Robert W. Wannemacher 1, Leonard A. Smith 1, Charles B. Millard 1*

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

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


  Abstract

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.

Keywords: Protein engineering, ribosome inactivating proteins, protein aggregation


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