Blocking copper transporter protein-dependent drug efflux with albumin-encapsulated Pt(IV) for synergistically enhanced chemo-immunotherapy DOI Creative Commons

Man Fang,

Lei Cao, Zhao Zhang

et al.

Research Square (Research Square), Journal Year: 2024, Volume and Issue: unknown

Published: Dec. 20, 2024

Abstract Non-small cell lung cancer (NSCLC) represents the most prevalent form of cancer, exerting a substantial impact on global health. Cisplatin-based chemotherapy is standard treatment for NSCLC, but resistance and severe side effects present significant clinical challenges. Recently, novel tetravalent platinum compounds have attracted interest. While numerous studies concentrate their functional modifications targeted delivery, tumor-induced frequently overlooked. Previous compound demonstrated antitumor activity, yet proved ineffective against cells exhibiting to cisplatin. In order enhance efficacy potential applications in glutathione (GSH)-responsive albumin nanoquadrivalent (HSA@Pt) been constructed. light previous research into drug conjugation, this study was develop combined chemo-immunotherapy approach. The HSA@Pt high low toxicity, with tumor accumulation. Furthermore, tetrathiomolybdate (TM) has exert synergistic inhibitory effect Cu2+ Transporting Beta Polypeptide (ATP7B) Programmed Death Ligand 1 (PD-L1), impede efflux, induce cellular stress, activate immunity. findings suggest HSA@Pt's use strategy enhancing utility established drugs through sensitization.

Language: Английский

Metal Ion Signaling in Biomedicine DOI Creative Commons
Raphaël Rodriguez, Sebastian Müller, Ludovic Colombeau

et al.

Chemical Reviews, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 2, 2025

Complex multicellular organisms are composed of distinct tissues involving specialized cells that can perform specific functions, making such life forms possible. Species defined by their genomes, and differences between individuals within a given species directly result from variations in genetic codes. While alterations give rise to disease-causing acquisitions cell identities, it is now well-established biochemical imbalances also lead cellular dysfunction diseases. Specifically, nongenetic chemical events orchestrate metabolism transcriptional programs govern functional identity. Thus, signaling, which broadly defines the conversion extracellular signals into intracellular changes, contribute acquisition diseased states. Metal ions exhibit unique properties be exploited cell. For instance, metal maintain ionic balance cell, coordinate amino acid residues or nucleobases altering folding function biomolecules, catalyze reactions. metals essential signaling effectors normal physiology disease. Deciphering ion challenging endeavor illuminate pathways targeted for therapeutic intervention. Here, we review key processes where play roles describe how targeting has been instrumental dissecting biochemistry this led development effective strategies.

Language: Английский

Citations

2
Non-hyperbolic enzyme kinetics: the case of P-type ATPases DOI
Santiago E. Faraj, Mónica R. Montes, R. Daniel Peluffo

et al.

Biophysical Reviews, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 11, 2025

Language: Английский

Citations

1
Copper homeostasis in Streptococcus and Neisseria: Known knowns and unknown knowns DOI
Anthony Howell,

Safa Chogule,

Karrera Y. Djoko

et al.

Advances in microbial physiology/Advances in Microbial Physiology, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 1, 2025

Language: Английский

Citations

0
Cracking Controls ATP Hydrolysis in the catalytic domain of a P-ATPase DOI Open Access
M. Agueda Placenti,

Santiago A. Martinez-Gache,

Rodolfo M. González‐Lebrero

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 30, 2025

Abstract Membrane transporters are essential for cell homeostasis. Among them P-type ATPases, which couple ATP hydrolysis to solute transport, play a key role. Despite extensive research, the fine mechanisms by this coupling occurs not completely understood. In work, we analyzed effect of substrate, temperature, and urea on steady state ATPase activity, tryptophan fluorescence far-UV ellipticity catalytic domain thermophilic Cu(I) transport ATPase. Through local frustration analysis in combination with AlphaFold2 prediction, identified novel conformation, enabling molecular dynamics simulations an open/close transition. Our results revealed “cracking” mechanism as step cycle. Furthermore, developed model that fully describes all experimental observations. These findings reinforce idea unfolding is involved enzyme catalysis suggest role regulation activity.

Language: Английский

Citations

0
Blocking copper transporter protein-dependent drug efflux with albumin-encapsulated Pt(IV) for synergistically enhanced chemo-immunotherapy DOI Creative Commons

Man Fang,

Lei Cao, Zhao Zhang

et al.

Journal of Nanobiotechnology, Journal Year: 2025, Volume and Issue: 23(1)

Published: March 18, 2025

Non-small cell lung cancer (NSCLC) represents the most prevalent form of cancer, exerting a substantial impact on global health. Cisplatin-based chemotherapy is standard treatment for NSCLC, but resistance and severe side effects present significant clinical challenges. Recently, novel tetravalent platinum compounds have attracted interest. While numerous studies concentrate their functional modifications targeted delivery, tumor-induced frequently overlooked. Previous compound demonstrated antitumor activity, yet proved ineffective against cells exhibiting to cisplatin. In order enhance efficacy potential applications in glutathione (GSH)-responsive albumin nanoquadrivalent (HSA@Pt) been constructed. light previous research into drug conjugation, this study was develop combined chemo-immunotherapy approach. The HSA@Pt high low toxicity, with tumor accumulation. Furthermore, Ammonium Tetrathiomolybdate (TM) has exert synergistic inhibitory effect ATPase Copper Transporting Beta (ATP7B) Programmed Death Ligand 1 (PD-L1), impede efflux, induce cellular stress, activate immunity. findings suggest HSA@Pt's use strategy enhancing utility established drugs through sensitization.

Language: Английский

Citations

0
Generative Landscapes and Dynamics to Design Multidomain Artificial Transmembrane Transporters DOI Creative Commons
Fernando Videgaray Ortega, Fahim Muhtasim Hossain,

Vladimir V. Volobouev

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: April 2, 2025

Protein design is challenging as it requires simultaneous consideration of interconnected factors, such fold, dynamics, and function. These evolutionary constraints are encoded in protein sequences can be learned through the latent generative landscape (LGL) framework to predict functional by leveraging patterns, enabling exploration uncharted sequence space. By simulating designed proteins molecular dynamics (MD), we gain deeper insights into interdependencies governing structure dynamics. We present a synergized workflow combining LGL with MD biochemical characterization, allowing us explore space effectively. This approach has been applied characterize two artificial multidomain ATP-driven transmembrane copper transporters, native-like functionality. integrative proved effective unraveling intricate relationships between sequence, structure,

Language: Английский

Citations

0
Emerging Perspectives of Copper-Mediated Transcriptional Regulation in Mammalian Cell Development DOI Creative Commons
Fa’alataitaua M. Fitisemanu, Teresita Padilla‐Benavides

Metallomics, Journal Year: 2024, Volume and Issue: 16(10)

Published: Oct. 1, 2024

Copper (Cu) is a vital micronutrient necessary for proper development and function of mammalian cells tissues. Cu mediates the redox active enzymes that facilitate metabolic processes signaling pathways. levels are tightly regulated by network Cu-binding transporters, chaperones, small molecule ligands. Extensive research has focused on homeostasis (cuprostasis) pathologies, which result from mutations perturbations. There roles proteins as transcription factors (Cu-TFs) regulators mediate metal through activation or repression genes associated with handling. Emerging evidence suggests some Cu-TFs may be involved in regulation targets related to development-expanding biological proteins. implicated embryonic tissue-specific alongside mediation cellular response oxidative stress hypoxia. also neurological disorders, providing new biomarkers therapeutic diseases such Parkinson's disease, prion Friedreich's ataxia. This review provides critical analysis current understanding role cuproproteins transcriptional regulation.

Language: Английский

Citations

3
In vitro reconstitution of transition metal transporters DOI Creative Commons
Elvis Legala Ongey, Anirban Banerjee

Journal of Biological Chemistry, Journal Year: 2024, Volume and Issue: 300(8), P. 107589 - 107589

Published: July 19, 2024

Language: Английский

Citations

2
Structural Basis of Ion Transport in Copper‐Transporting P IB ‐Type ATPases DOI
Viktoria Bågenholm, Pontus Gourdon

Encyclopedia of Inorganic and Bioinorganic Chemistry, Journal Year: 2024, Volume and Issue: unknown, P. 1 - 12

Published: Sept. 18, 2024

Abstract Maintaining correct copper levels is vital for all cells, as required a large number of cellular processes, but also toxic due to its high reactivity. Such regulation accomplished using range including the P IB‐1 ‐subgroup P‐type ATPases. These primary active transporters exploit ATP shuttle across membranes, either out cell or into various organelles use, such incorporation copper‐dependent proteins. The pumping membrane follows conserved scheme, called Post‐Albers cycle, where protein cycles through series states, from inward‐open (E1) inward‐occluded (E1P), outward‐open (E2P), and outward‐occluded (E2) back, coupled phosphorylation by dephosphorylation. This established via core consisting three soluble A‐, P‐, N‐domains, transmembrane domain formed eight membrane‐spanning helices, MA, MB, M1–M6, well varying metal‐binding domains MBDs, which typically are part N‐terminus. Copper delivered ‐transporter small molecule chaperones inside cytoplasm, likely assisted an MBD. metal then transferred methionine M1 at interface, relocates it two cysteines CPC motif in M4. Next, one high‐affinity‐binding sites M‐domain, again utilizing methionines. Finally, release achieved outward‐facing exit tunnel lined While much this pathway has been elucidated determined molecular structures, important questions remain, example, regarding roles MBDs. Here, structural details transport ‐type ATPases will be described.

Language: Английский

Citations

0
Blocking copper transporter protein-dependent drug efflux with albumin-encapsulated Pt(IV) for synergistically enhanced chemo-immunotherapy DOI Creative Commons

Man Fang,

Lei Cao, Zhao Zhang

et al.

Research Square (Research Square), Journal Year: 2024, Volume and Issue: unknown

Published: Dec. 20, 2024

Abstract Non-small cell lung cancer (NSCLC) represents the most prevalent form of cancer, exerting a substantial impact on global health. Cisplatin-based chemotherapy is standard treatment for NSCLC, but resistance and severe side effects present significant clinical challenges. Recently, novel tetravalent platinum compounds have attracted interest. While numerous studies concentrate their functional modifications targeted delivery, tumor-induced frequently overlooked. Previous compound demonstrated antitumor activity, yet proved ineffective against cells exhibiting to cisplatin. In order enhance efficacy potential applications in glutathione (GSH)-responsive albumin nanoquadrivalent (HSA@Pt) been constructed. light previous research into drug conjugation, this study was develop combined chemo-immunotherapy approach. The HSA@Pt high low toxicity, with tumor accumulation. Furthermore, tetrathiomolybdate (TM) has exert synergistic inhibitory effect Cu2+ Transporting Beta Polypeptide (ATP7B) Programmed Death Ligand 1 (PD-L1), impede efflux, induce cellular stress, activate immunity. findings suggest HSA@Pt's use strategy enhancing utility established drugs through sensitization.

Language: Английский

Citations

0