Codominant interference, antieffectors, and multitarget drugs.

Abstract

The insufficient selectivity of drugs is a bane of present-day therapies. This problem is significant for antibacterial drugs, difficult for antivirals, and utterly unsolved for anticancer drugs, which remain ineffective against major cancers, and in addition cause severe side effects. The problem may be solved if a therapeutic agent could have a multitarget, combinatorial selectivity, killing, or otherwise modifying, a cell if and only if it contains a predetermined set of molecular targets and lacks another predetermined set of targets. An earlier design of multitarget drugs [Varshavsky, A. (1995) Proc. Natl. Acad. Sci. USA 92, 3663-3667] was confined to macromolecular reagents such as proteins, with the attendant difficulties of intracellular delivery and immunogenicity. I now propose a solution to the problem of drug selectivity that is applicable to small (</=1 kDa) drugs. Two ideas, codominant interference and antieffectors, should allow a therapeutic regimen to possess combinatorial selectivity, in which the number of positively and negatively sensed macromolecular targets can be two, three, or more. The nature of the effector and interference moieties in a multitarget drug determines its use: selective killing of cancer cells or, for example, the inhibition of a neurotransmitter-inactivating enzyme in a specific subset of the enzyme-containing cells. The in vivo effects of such drugs would be analogous to the outcomes of the Boolean operations "and," "or," and combinations thereof. I discuss the logic and applications of the antieffector and interference/codominance concepts, and the attendant problem of pharmacokinetics.