Codominance and toxins: a path to drugs of nearly unlimited selectivity.
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 P1 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.
Varshavsky
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Division of Biology, California Institute of Technology, Pasadena 91125, USA.
D036002:ADP Ribose Transferases; D000818:Animals; D001427:Bacterial Toxins; D001692:Biological Transport; D002470:Cell Survival / Q000187:drug effects*; D004167:Diphtheria Toxin / Q000378:metabolism / Q000633:toxicity; D015195:Drug Design; D005098:Exotoxins / Q000378:metabolism / Q000633:toxicity; D005260:Female; D006801:Humans; D008928:Mitochondria / Q000187:drug effects / Q000473:pathology; D015388:Organelles / Q000187:drug effects / Q000473:pathology; D011506:Proteins / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity*; D011550:Pseudomonas aeruginosa; D013329:Structure-Activity Relationship; D014118:Toxins, Biological / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity*; D037521:Virulence Factors; D000097668:Pseudomonas aeruginosa Exotoxin A
D036002:ADP Ribose Transferases; D001427:Bacterial Toxins; D004167:Diphtheria Toxin; D005098:Exotoxins; D011506:Proteins; D014118:Toxins, Biological; D037521:Virulence Factors; D000097668:Pseudomonas aeruginosa Exotoxin A