DNA as a target

DNA is not only the central molecule of life but also a target for cancer therapy. If cellular DNA is damaged beyond repair, cells initiate self-programmed death, or apoptosis. If one can limit this process to cancer cells and make them will self-destruct selectively, efficient DNA damage can be used for the development of anticancer agents.  Not surprisingly, natural enediyne antibiotics,  molecules hailed as "the most efficient anticancer agents" known to date utilize DNA damage as is the key step in the mechanism of their biological activity.

Selectivity and efficiency are the most important questions in the design of DNA-cleaving agents for cancer therapy. How can one limit the damage to the cancerous cells without affecting the healthy tissue? How can one overpower the efficient DNA repair mechanisms which usually reverse the damage and keep our genome functioning for many years?

 The astounding biological activity of natural enediyne antibiotics is associated with their ability to cause simultaneous damage of both DNA strands ("the doble stranded" or "ds" DNA cleavage). Although even the best of natural enediynes, calicheamicin, induces, at best, ~25-33% of the double stranded cleavage, this is still enough to  account for the record-breaking biological activity of enediynes (and also set a world record for ds:ss (single-strand) DNA cleavage ratio for a non-enzymatic molecule).

Unlike the readily repairable single-strand ("ss") DNA cleavage where the two DNA strands are still kept together with hydrogen  bonding,   DNA with both strands broken is much more difficult "patient" for repair enzyme (the little repairman shown on the left). As the result, even moderately efficient ds DNA cleavage may lead to the highly efficient apoptosis.  

Our group developed a family of light-activated molecules with the ds-DNA cleavage efficiency rivaling (for the first generation) or exceeding (for the second generation) the ds:ss ratio of calichiamicin. Not only the use of light allows us to activate our molecules exactly at the right time and right place, inside of the cancer cells but, remarkably, the unprecedently high efficiency of ds-DNA cleavage is observed under slighly acidic conditions suitable for selective targeting of certain cancers.

Photochemical conversion of ss DNA damage to ds DNA damage

We have developed the first light-activated molecular system which can convert easily repairable ss DNA cleavage into ds DNA cleavage (read more: the original work, press-release, media coverage...)

pH-Gated light-activated reagents for ds-DNA cleavage

In our design, we combined efficient DNA-cleaver capable of operating within the physiological pH range with a pH-controlled part which allows us to "switch on" the reactivity at a relatively narrow and predefined pH point close to the threshold between cancerous and healthy cells (read more..).

 At pH 5.5, we observe up to 50% of ds DNA cleavage. Remarkably, at the same concentrations and pH of healthy cells (pH 7.2), almost no double stranded damage is observed!