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Codominance and toxins: A path to drugs of nearly unlimited selectivity

Varshavsky, Alexander (1995) Codominance and toxins: A path to drugs of nearly unlimited selectivity. Proceedings of the National Academy of Sciences of the United States of America, 92 (9). pp. 3663-3667. ISSN 0027-8424. PMCID PMC42021. doi:10.1073/pnas.92.9.3663.

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The effectiveness of drugs is often limited by their insufficient selectivity. I propose designs of therapeutic agents that address this problem. The key feature of these reagents, termed comtoxins (codominance-mediated toxins), is their ability to utilize codominance, a property characteristic of many signals in proteins, including degradation signals (degrons) and nuclear localization signals. A comtoxin designed to kill cells that express intracellular proteins P1 and P2 but to spare cells that lack P1 and/or P2 is a multidomain fusion containing a cytotoxic domain and two degrons placed within or near two domains P1* and P2* that bind, respectively, to pi and P2. In a cell containing both P1 and P2, these proteins would bind to the P1* and P2* domains of the comtoxin and sterically mask the nearby (appropriately positioned) degrons, resulting in a long-lived and therefore toxic drug. By contrast, in a cell lacking P1 and/or P2, at least one of the comtoxin's degrons would be active (unobstructed), yielding a short-lived and therefore nontoxic drug. A comtoxin containing both a degron and a nuclear localization signal can be designed to kill exclusively cells that contain P1 but lack P2. Analogous strategies yield comtoxins sensitive to the presence (or absence) of more than two proteins in a cell. Also considered is a class of comtoxins in which a toxic domain is split by a flexible insert containing binding sites for the target proteins. The potentially unlimited, combinatorial selectivity of comtoxins may help solve the problem of side effects that bedevils present-day therapies, for even nonselective delivery of a comtoxin would not affect cells whose protein "signatures" differ from the targeted one.

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Varshavsky, Alexander0000-0002-4011-258X
Additional Information:© 1995 by the National Academy of Sciences. Communicated by John N. Abelson, California Institute of Technology, Pasadena, CA, December 19, 1994. I thank C. Byrd, M. Ghislain, N. Johnsson, Y.-T. Kwon, F. Levy, A. Rich, and especially G. Turner for their comments on the manuscript. The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.
Issue or Number:9
PubMed Central ID:PMC42021
Record Number:CaltechAUTHORS:VARpnas95
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Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:1404
Deposited By: Tony Diaz
Deposited On:17 Jan 2006
Last Modified:08 Nov 2021 19:10

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