Profiling a multiactions folic acid-octapeptide conjugate to gain anticancer selectivity

Author(s): Maria Paola Costi

 Bio A rational design of lead compounds that takes into account their cellular internalization and paths to the targets increases the probability of success in the pharmacokinetic tests to be run in the following stages of lead optimization. In our approach we demonstrate how a computational and chemical-biological integrated approach may yield conjugates of drug leads with improved selectivity. Folic acid is present in human body and physiologically enter the cells through a few different transporters such as folate receptors and reduced folate carriers. These transporters are differentially expressed in normal and cancer cells, therefore characterizing sub-populations that may be subjected to personalized therapy. To take advantage of the mentioned cell specificities, we have designed and synthesized the conjugates of folic acid (FA) with two anticancer octapeptides with the goal of building molecular entities that, on one hand, would exploit the FA moiety to enter cancer cells through the folate receptor α (FRα) or other FA-based transporters and, on the other hand, would employ the peptidic moiety to inhibit intracellular human thymidylate synthase (hTS) by an unconventional mechanism that, not inducing over-expression of the enzyme, helps in avoiding the onset of drug resistance. In one single molecular entity we combine high value biological effects such as selective targeting, innovative on-target mechanism of action and drug resistance decreases. In our studies molecular modeling simulations have shown that, consistently with their difunctional nature, these conjugates feature a complex hTS inhibition mechanism, by binding at the monomer-monomer interface of this dimeric protein through their peptidic moieties. The two bioconjugates have shown cellular growth inhibition levels similar to those of known TS-targeted drugs and were also active towards cisplatin-resistant ovarian cancer cells that overexpress FR∝Biological markers indicate their cellular mechanism of action to be different from that of classical TS inhibitors. 


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