Molecular Logic as a Means to Assess Therapeutic Antidotes

Abstract

An emerging direction in the area of molecular logic and computation is developing molecular-scale devices that can operate in complex biological environments, such as within living cells, which are beyond the reach of conventional electronic devices. Herein we demonstrate, at the proof-of-principle level, how concepts applied in the field of molecular logic gates can be used to convert a simple fluorescent switch (YES gate), which lights up in the presence of glutathione s-transferase (GST), into a medicinally relevant INHIBIT gate that responds to both GST and beta-cyclodextrin (β-CD) as input signals. We show that the optical responses generated by this device indicate the ability to use it as an enzyme inhibitor, and more importantly, the ability to use β-CD as an “antidote” that prevents GST inhibition. The relevance of this system to biomedical applications is demonstrated by using the INHIBIT gate and β-CD to regulate the growth of breast cancer cells, highlighting the possibility of applying supramolecular inputs, commonly used to control the fluorescence of molecular logic gates, as antidotes that reverse the toxic effect of chemotherapy agents. We also show that the effect of β-CD can be prevented by introducing 1-adamantanecarboxylic acid (Ad-COOH) as an additional input signal, indicating the potential of obtaining precise, temporal control over enzyme activity and anticancer drug function.

Elucidating sensing mechanisms of a pyrene excimer-based calix[4]arene for ratiometric detection of Hg(ii) and Ag(i) and chemosensor behaviour as INHIBITION or IMPLICATION logic gates

“…Fluorescent chemosensors that are able to perform logic operations have attracted much attention due to its potential applications in biosensing and diagnosis, contaminant determination or molecular computation. [80][81][82] In general, their application as molecular logic gates is possible when two or more inputs give different uorescent outputs or sensing mechanism as unveiled our results. Among the sixteen Boolean operations that can be congured, six of them are rather trivial in terms of uorescent output or molecular design.…”

Development of dual enzyme responsive molecular AND logic gate

“…Later, the idea is used to develop many different advanced logic gates such as DEMUX, FLIP-FLOP logics as well as integrated logic gates [ 5 ]. Some of these logic gates are shown to have potential applications as smart therapeutics or biosensors [ 6 – 20 ]. Recently, our research group designed a molecular keypad lock to show that information processing devices can have selective therapeutic activity in drug-resistant cancer cells, through a sequential analyte responsiveness and molecular encryption [ 6 ].…”

A therapeutic keypad lock decoded in drug resistant cancer cells

“…8 Selective drug activation, release, multiple-analyte sensing and theranostic applications of these devices have been explored by us and others. 5,[9][10][11][12][13][14][15][16][17][18][19] Among the operations that can be carried out using small molecules, keypad locks provide an alternative application in information security. 20 This logic operation can give a specic output when the inputs are given in the correct form and correct sequence.…”