BackgroundTamoxifen is the standard endocrine therapy for breast cancers, which require metabolic activation by cytochrome P450 enzymes (CYP). However, the lower and variable concentrations of CYP activity at the tumor remain major bottlenecks for the efficient treatment, causing severe side-effects. Combination nanotherapy has gained much recent attention for cancer treatment as it reduces the drug-associated toxicity without affecting the therapeutic response.ResultsHere we show the modular design of P22 bacteriophage virus-like particles for nanoscale integration of virus-driven enzyme prodrug therapy and photodynamic therapy. These virus capsids carrying CYP activity at the core are decorated with photosensitizer and targeting moiety at the surface for effective combinatory treatment. The estradiol-functionalized nanoparticles are recognized and internalized into ER+ breast tumor cells increasing the intracellular CYP activity and showing the ability to produce reactive oxygen species (ROS) upon UV365 nm irradiation. The generated ROS in synergy with enzymatic activity drastically enhanced the tamoxifen sensitivity in vitro, strongly inhibiting tumor cells.ConclusionsThis work clearly demonstrated that the targeted combinatory treatment using multifunctional biocatalytic P22 represents the effective nanotherapeutics for ER+ breast cancer.Electronic supplementary materialThe online version of this article (10.1186/s12951-018-0345-2) contains supplementary material, which is available to authorized users.
Lactate dehydrogenase (LDH) catalyzes the reduction of pyruvate to lactate by using NADH. LDH kinetics has been proposed to be dependent on the dynamics of a loop over the active site. Kramers' theory has been useful in the study of enzyme catalysis dependent on large structural dynamics. In this work, LDH kinetics was studied in the presence of trehalose and at different temperatures. In the absence of trehalose, temperature increase raised exponentially the LDH V and revealed a sigmoid transition of K toward a low-affinity state similar to protein unfolding. Notably, LDH V diminished when in the presence of trehalose, while pyruvate affinity increased and the temperature-mediated binding site transition was hindered. The effect of trehalose on k was viscosity dependent as described by Kramers' theory since V correlated inversely with the viscosity of the medium. As a result, activation energy ( E) for pyruvate reduction was dramatically increased by trehalose presence. This work provides experimental evidence that the dynamics of a structural component in LDH is essential for catalysis, i.e., the closing of the loop on the active site. While the trehalose mediated-increased of pyruvate affinity is proposed to be due to the compaction and/or increase of structural order at the binding site.
Inhibition of the expression of the human ether-a-go-go (hEAG1 or hK V 10.1) channel is associated with a dramatic reduction in the growth of several cancerous tumors. The modulation of this channel's activity is a promising target for the development of new anticancer drugs. Although some small molecules have shown inhibitory activity against K V 10.1, their lack of specificity has prevented their use in humans. In vitro studies have recently identified a limited number of peptide toxins with proven specificity in their hK V 10.1 channel inhibitory effect. These peptide toxins have become desirable candidates to use as lead compounds to design more potent and specific hK V 10.1 inhibitors. However, the currently available studies lack the atomic resolution needed to characterize the molecular features that favor their binding to hK V 10.1. In this work, we present the first attempt to locate the possible hK V 10.1 binding sites of the animal peptide toxins APETx4, Aa1a, Ap1a, and khefutoxin 1, all of which described as hK V 10.1 inhibitors. Our studies incorporated homology modeling to construct a robust three-dimensional (3D) model of hK V 10.1, applied protein docking, and multiscale molecular dynamics techniques to reveal in atomic resolution the toxin−channel interactions. Our approach suggests that some peptide toxins bind in the outer vestibule surrounding the pore of hK V 10.1; it also identified the channel residues Met397 and Asp398 as possible anchors that stabilize the binding of the evaluated toxins. Finally, a description of the possible mechanism for inhibition and gating is presented.
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