Abstract
Drug–target interaction, cellular internalization, and target engagement should be addressed to design a lead with high chances of success in further optimization stages. Accordingly, we have designed conjugates of folic acid with anticancer peptides able to bind human thymidylate synthase (hTS) and enter cancer cells through folate receptor α (FRα) highly expressed by several cancer cells. Mechanistic analyses and molecular modeling simulations have shown that these conjugates bind the hTS monomer–monomer interface with affinities over 20 times larger than the enzyme active site. When tested on several cancer cell models, these conjugates exhibited FRα selectivity at nanomolar concentrations. A similar selectivity was observed when the conjugates were delivered in synergistic or additive combinations with anticancer agents. At variance with 5-fluorouracil and other anticancer drugs that target the hTS catalytic pocket, these conjugates do not induce overexpression of this protein and can thus help combating drug resistance associated with high hTS levels.
Highlights
A holistic approach to drug discovery takes into account the predictable multitarget interactions and focuses on both cellular internalization of the potential drug and its intracellular binding to on- and off-targets
We have designed the conjugates of folic acid, FA, with two peptides, LSCQLYQR (LR) and [DGln4]LR, with the aim to selectively internalize the FA−peptide conjugates in cancer cells through the folate receptor α (FRα)’s
While, through its peptidic moiety, a conjugate can bind the enzyme at the monomer−monomer interface of the inactive form, the FA moiety might directly bind at the folate binding site in the catalytic pocket of the enzyme.[2,7]
Summary
A holistic approach to drug discovery takes into account the predictable multitarget interactions and focuses on both cellular internalization of the potential drug and its intracellular binding to on- and off-targets. As previously mentioned, docking the conjugates at the binding site in the hTS active conformation in the presence of dUMP turned out to be more difficult in the case of FA−LR and not possible with FA−[DGln4]LR The FA− [DGln4]LR conjugate showed a slightly yet consistently higher activity toward IGROV-1 than toward TOV112D cells (Figure 8, right), a finding likely related with the higher expression of FRα in the former cells (see Figure 5 and the corresponding paragraph) The best results, with two synergistic SQ values, were obtained with the FRα-overexpressing IGROV-1 cells, indicating the potential of these combinations for targeting cancer cells with higher FRα levels
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