Wrapping Drug Combinations for Therapeutic Editing of Side Effects: Systems Biology Meets Wrapping Technology

Abstract

Wrapping designs have limitations arising from similarities in the biomolecular interfaces of on-target and off-target homologous proteins and also from the highly diverse cellular contexts wherein a protein may constitute a desirable or undesirable target. While dehydron wrapping enables the control of specificity, it may not be able to exclude every single toxicity-related target, especially if the latter shares with the therapeutically relevant targets a similar dehydron pattern in the drug-binding region. In such circumstances, we may need to resort to a multicomponent therapy where one drug acts synergistically with the other while selectively antagonizing it in the specific cellular context where the action of the first drug promotes toxicity. This chapter explores these a-priori therapeutic possibilities. As previously described, due to their ability to interfere with signal transduction events controlling cell proliferation and fate, kinase inhibitors hold promise as anticancer agents. Nevertheless, the functional role of a kinase depends on the cellular context and hence kinase inhibition in an off-target cell may lead to undesired side effects. Motivated by these observations, we explore a mode of “therapeutic editing” where one drug—the editor—suppresses the side effect promoted by the primary drug as it impacts off-target cells. Editor and primary drug have overlapping therapeutic impact, while the editor suppresses the downstream propagation of toxicity-related signaling triggered by the primary drug in an off-target cellular context.