Targeting human telomeric G-quadruplex DNA with curcumin and its synthesized analogues under molecular crowding conditions

The formation of telomeric G-quadruplexes has been shown to inhibit telomerase activity. Indeed, a number of small molecules capable of p-stacking with G-tetrads have shown the ability to inhibit telomerase activity through the stabilization of G-quadruplexes. Curcumin displays a wide spectrum of medicinal properties ranging from anti-bacterial, anti-viral, anti-protozoal, anti-fungal and anti-inflammatory to anti-cancer activity. We have investigated the interactions of curcumin and its structural analogues with the human telomeric sequence AG3(T2AG3)3 under molecular crowding conditions. Experimental studies indicated the existence of a AG3(T2AG3)3/curcumin complex with binding affinity of 0.72 � 106 M1 under molecular crowding conditions. The results from UV-visible absorption spectroscopy, a fluorescent TO displacement assay, circular dichroism and molecular docking studies, imply that curcumin and their analogues interact with G-quadruplex DNA via groove binding. While other analogs of curcumin studied here bind to G-quadruplexes in a qualitatively similar manner their affinities are relatively lower in comparison to curcumin. The Knoevenagel condensate, a methoxy-benzylidene derivative of curcumin, also exhibited significant binding to G-quadruplex DNA, although with two times decreased affinity. Our study establishes the potential of curcumin as a promising natural product for G-quadruplex specific ligands

An allosteric inhibitor of Mycobacterium tuberculosis ArgJ: Implications to a novel combinatorial therapy

The existing treatment regime against tuberculosis is not adequate, and novel therapeutic interventions are required to target Mycobacterium tuberculosis (Mtb) pathogenesis. We report Pranlukast (PRK) as a novel allosteric inhibitor of Mtb's arginine biosynthetic enzyme, Ornithine acetyltransferase (MtArgJ). PRK treatment remarkably abates the survival of free as well as macrophage-internalized Mtb, and shows enhanced efficacy in combination with standard-of-care drugs. Notably, PRK also reduces the 5-lipoxygenase (5-LO) signaling in the infected macrophages, thereby surmounting an enhanced response against intracellular pathogen. Further, treatment with PRK alone or with rifampicin leads to significant decrease in Mtb burden and tubercular granulomas in Mtb-infected mice lungs. Taken together, this study demonstrates a novel allosteric inhibitor of MtArgJ, which acts as a dual-edged sword, by targeting the intracellular bacteria as well as the bacterial pro-survival signaling in the host. PRK is highly effective against invitro and invivo survival of Mtb and being an FDA-approved drug, it shows a potential for development of advanced combinatorial therapy against tuberculosis

Targeting human telomeric G-quadruplex DNA with curcumin and its synthesized analogues under molecular crowding conditions

The formation of telomeric G-quadruplexes has been shown to inhibit telomerase activity. Indeed, a number of small molecules capable of p-stacking with G-tetrads have shown the ability to inhibit telomerase activity through the stabilization of G-quadruplexes. Curcumin displays a wide spectrum of medicinal properties ranging from anti-bacterial, anti-viral, anti-protozoal, anti-fungal and anti-inflammatory to anti-cancer activity. We have investigated the interactions of curcumin and its structural analogues with the human telomeric sequence AG(3)(T(2)AG(3))(3) under molecular crowding conditions. Experimental studies indicated the existence of a AG(3)(T(2)AG(3))(3)/curcumin complex with binding affinity of 0.72 x 10(6) M-1 under molecular crowding conditions. The results from UV-visible absorption spectroscopy, a fluorescent TO displacement assay, circular dichroism and molecular docking studies, imply that curcumin and their analogues interact with G-quadruplex DNA via groove binding. While other analogs of curcumin studied here bind to G-quadruplexes in a qualitatively similar manner their affinities are relatively lower in comparison to curcumin. The Knoevenagel condensate, a methoxy-benzylidene derivative of curcumin, also exhibited significant binding to G-quadruplex DNA, although with two times decreased affinity. Our study establishes the potential of curcumin as a promising natural product for G-quadruplex specific ligands