Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

A protein therapeutic modality founded on molecular regulation.

ABSTRACT: The exquisite specificity of proteins is a key feature driving their application to anticancer therapies. The therapeutic potential of another fundamental property of proteins, their ability to be regulated by molecular cues in their environment, is unknown. Here, we describe a synthetic biology strategy for designing protein therapeutics that autonomously activate a therapeutic function in response to a specific cancer marker of choice. We demonstrate this approach by creating a prodrug-activating enzyme that selectively kills human cancer cells that accumulate the marker hypoxia-inducible factor 1?. This property arises primarily through increased cellular accumulation of the enzyme in the presence of the marker. Our strategy offers a platform for the development of inherently selective protein therapeutics for cancer and other diseases.

SUBMITTER: Wright CM

PROVIDER: S-EPMC3182702 | biostudies-literature | 2011 Sep

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Publications

A protein therapeutic modality founded on molecular regulation.

Wright Chapman M CM Wright R Clay RC Eshleman James R JR Ostermeier Marc M

Proceedings of the National Academy of Sciences of the United States of America 20110919 39

The exquisite specificity of proteins is a key feature driving their application to anticancer therapies. The therapeutic potential of another fundamental property of proteins, their ability to be regulated by molecular cues in their environment, is unknown. Here, we describe a synthetic biology strategy for designing protein therapeutics that autonomously activate a therapeutic function in response to a specific cancer marker of choice. We demonstrate this approach by creating a prodrug-activat ...[more]

PMID: 21930952

Similar Datasets

Evolution of Cereblon-Mediated Protein Degradation as a Therapeutic Modality.

Project description:Many cellular processes and pathways are mediated by the regulation of protein-protein complexes. For example, E3 ubiquitin ligases recruit substrate proteins and transfer a ubiquitin tag to target those proteins for destruction by the proteasome. It has now been shown that this cellular process for protein destruction can be redirected by small molecules in both laboratory and clinical settings. This presents a new paradigm in drug discovery, enabling the rapid removal of target proteins linked to disease. In this Innovations review, we will describe the work done on cereblon as a case study on the different strategies available for targeted protein degradation.

| S-EPMC6912861 | biostudies-literature

Focused Ultrasound: An Emerging Therapeutic Modality for Neurologic Disease.

Project description:Therapeutic ultrasound is only beginning to be applied to neurologic conditions, but the potential of this modality for a wide spectrum of brain applications is high. Engineering advances now allow sound waves to be targeted through the skull to a brain region selected with real time magnetic resonance imaging and thermography, using a commercial array of focused emitters. High intensities of sonic energy can create a coagulation lesion similar to that of older radiofrequency stereotactic methods, but without opening the skull. This has led to the recent Food and Drug Administration approval of focused ultrasound (FUS) thalamotomy for unilateral treatment of essential tremor. Clinical studies of stereotactic FUS for aspects of Parkinson's disease, chronic pain, and refractory psychiatric indications are underway, with promising results. Moderate-intensity FUS has the potential to safely open the blood-brain barrier for localized delivery of therapeutics, while low levels of sonic energy can be used as a form of neuromodulation.

| S-EPMC5398988 | biostudies-literature

Targeting chelatable iron as a therapeutic modality in Parkinson's disease.

Project description:The pathophysiological role of iron in Parkinson's disease (PD) was assessed by a chelation strategy aimed at reducing oxidative damage associated with regional iron deposition without affecting circulating metals. Translational cell and animal models provided concept proofs and a delayed-start (DS) treatment paradigm, the basis for preliminary clinical assessments.For translational studies, we assessed the effect of oxidative insults in mice systemically prechelated with deferiprone (DFP) by following motor functions, striatal dopamine (HPLC and MRI-PET), and brain iron deposition (relaxation-R2*-MRI) aided by spectroscopic measurements of neuronal labile iron (with fluorescence-sensitive iron sensors) and oxidative damage by markers of protein, lipid, and DNA modification. DFP significantly reduced labile iron and biological damage in oxidation-stressed cells and animals, improving motor functions while raising striatal dopamine. For a pilot, double-blind, placebo-controlled randomized clinical trial, early-stage Parkinson's patients on stabilized dopamine regimens enrolled in a 12-month single-center study with DFP (30 mg/kg/day). Based on a 6-month DS paradigm, early-start patients (n=19) compared to DS patients (n=18) (37/40 completed) responded significantly earlier and sustainably to treatment in both substantia nigra iron deposits (R2* MRI) and Unified Parkinson's Disease Rating Scale motor indicators of disease progression (p<0.03 and p<0.04, respectively). Apart from three rapidly resolved neutropenia cases, safety was maintained throughout the trial.A moderate iron chelation regimen that avoids changes in systemic iron levels may constitute a novel therapeutic modality for PD.The therapeutic features of a chelation modality established in translational models and in pilot clinical trials warrant comprehensive evaluation of symptomatic and/or disease-modifying potential of chelation in PD.

| S-EPMC4060813 | biostudies-literature

Chronotherapy: Intuitive, Sound, Founded…But Not Broadly Applied.

Project description:Circadian rhythms are a collection of endogenously driven biochemical, physiological, and behavioral processes that oscillate in a 24-h cycle and can be entrained by external cues. Circadian clock molecules are responsible for the expression of regulatory components that modulate, among others, the cell's metabolism and energy consumption. In clinical practice, the regulation of clock mechanisms is relevant to biotransformation of therapeutics. Accordingly, xenobiotic metabolism and detoxification, the two processes that directly influence drug effectiveness and toxicity, are direct manifestations of the daily oscillations of the cellular and biochemical processes taking place within the gastrointestinal, hepatic/biliary, and renal/urologic systems. Consequently, the impact of circadian timing should be factored in when developing therapeutic regimens aimed at achieving maximum efficacy, minimum toxicity, and decreased adverse effects in a patient. However, and despite a strong mechanistic foundation, only 0.16 % of ongoing clinical trials worldwide exploit the concept of 'time-of-day' administration to develop safer and more effective therapies. In this article, we (1) emphasize points of control at which circadian biology intersects critical processes governing treatment interventions; (2) explore the extent to which chronotherapeutics are incorporated into clinical trials; (3) recognize roadblocks; and (4) recommend approaches to precipitate the integration of chronobiological concepts into clinical practice.

| S-EPMC5082589 | biostudies-literature

Androgen/Androgen Receptor Signaling in Ovarian Cancer: Molecular Regulation and Therapeutic Potentials.

Project description:Ovarian cancer (OVCA) arises from three cellular origins, namely surface epithelial cells, germ cells, and stromal cells. More than 85% of OVCAs are EOCs (epithelial ovarian carcinomas), which are the most lethal gynecological malignancies. Cancer stem/progenitor cells (CSPCs) are considered to be cancer promoters due to their capacity for unlimited self-renewal and drug resistance. Androgen receptor (AR) belongs to the nuclear receptor superfamily and can be activated through binding to its ligand androgens. Studies have reported an association between AR expression and EOC carcinogenesis, and AR is suggested to be involved in proliferation, migration/invasion, and stemness. In addition, alternative AR activating signals, including both ligand-dependent and ligand-independent, are involved in OVCA progression. Although some clinical trials have previously been conducted to evaluate the effects of anti-androgens in EOC, no significant results have been reported. In contrast, experimental studies evaluating the effects of anti-androgen or anti-AR reagents in AR-expressing EOC models have demonstrated positive results for suppressing disease progression. Since AR is involved in complex signaling pathways and may be expressed at various levels in OVCA, the aim of this article was to provide an overview of current studies and perspectives regarding the relevance of androgen/AR roles in OVCA.

| S-EPMC8304547 | biostudies-literature

Hydrodissection as a therapeutic and diagnostic modality in treating peroneal nerve compression.

Project description:A 51-year-old man presented with pain in the region of his left patellar tendon and fibular head. He had previously undergone three L5 epidural steroid injections and physical therapy without relief. Prior magnetic resonance imaging was significant only for fat pad impingement, and electromyography and nerve conduction studies were negative. Ultrasound demonstrated an enlarged peroneal nerve suggestive of peroneal nerve entrapment. Three ultrasound-guided hydrodissection procedures offered symptomatic improvement and identified an area posterior to the fibular head that was unable to be hydrodissected, indicating scar tissue causing peroneal nerve compression. The patient was referred for peroneal nerve decompression at the area of entrapment with complete symptom relief. This case is unique in describing the ability of hydrodissection to identify nerve compression not visualized with other diagnostic tests.

| S-EPMC7340467 | biostudies-literature

Dynamic Regulation of APE1/Ref-1 as a Therapeutic Target Protein.

Project description:Apurinic/apyrimidinic endonuclease 1/redox factor-1 (APE1/Ref-1) is a multifunctional protein that plays a central role in the cellular response to DNA damage and redox regulation against oxidative stress. APE1/Ref-1 functions in the DNA base excision repair pathway, the redox regulation of several transcription factors, and the control of intracellular redox status through the inhibition of reactive oxygen species (ROS) production. APE1/Ref-1 is predominantly localized in the nucleus; however, its subcellular localization is dynamically regulated and it may be found in the mitochondria or elsewhere in the cytoplasm. Studies have identified a nuclear localization signal and a mitochondrial target sequence in APE1/Ref-1, as well as the involvement of the nuclear export system, as determinants of APE1/Ref-1 subcellular distribution. Recently, it was shown that APE1/Ref-1 is secreted in response to hyperacetylation at specific lysine residues. Additionally, post-translational modifications such as phosphorylation, S-nitrosation, and ubiquitination appear to play a role in fine-tuning the activities and subcellular localization of APE1/Ref-1. In this review, we will introduce the multifunctional role of APE1/Ref-1 and its potential usefulness as a therapeutic target in cancer and cardiovascular disease.

| S-EPMC4880582 | biostudies-literature

Metabolic manipulators: a well founded strategy to combat mitochondrial dysfunction.

Project description:Whilst the pathophysiology and genetics of mitochondrial disease are slowly being unraveled, currently no effective remedy for mitochondrial disorders is available. One particular strategy in mitochondrial medicine presently under study is metabolic manipulation. This approach is aimed at counteracting the deranged cell biological homeostasis caused by mitochondrial dysfunction, using dietary modifications or small molecule therapy. Cell biological alterations caused by mitochondrial dysfunction include increased reactive oxygen species production, enhanced lipid peroxidation and altered cellular calcium homeostasis. This review covers the five principles of metabolic manipulation: (1) prevention of oxidative damage by reactive oxygen species, (2) amelioration of lipid peroxidation, (3) correction of altered membrane potential, (4) restoration of calcium homeostasis, and (5) transcription regulation interference. We hypothesize that a combination of compounds targeting different metabolic pathways will abolish cellular disturbance arising as a consequences of mitochondrial dysfunction, and thereby improve or stabilize clinical features. However, only a handful of compounds have reached efficacy testing in mammals, and it remains unknown to what extent metabolic manipulation will affect the whole organism. Until a potent remedy is found, patients will remain dependent on supportive, not curative, interventions.

| S-EPMC3063543 | biostudies-literature

Antiviral peptide nanocomplexes as a potential therapeutic modality for HIV/HCV co-infection.

Project description:It is estimated that 4 to 5 million people are currently co-infected with Human Immunodeficiency Virus (HIV) and Hepatitis C Virus (HCV). HIV/HCV co-infection is associated with unique health risks including increased hepatotoxicity of antiretrovirals, accelerated progression of HCV and liver diseases. The standard interferon-based therapy is effective only in about 50% of patients and often is associated with autoimmune and neuro-psychiatric complications. The treatment of co-infection (HIV/HCV) requires new strategic approaches. To this end, the formulations of an amphiphatic α-helical peptide, a positively charged analog of C5A peptide derived from the HCV NS5A protein, with a reported virocidal activity were prepared by electrostatic coupling with anionic poly(amino acid)-based block copolymers. The self-assembled antiviral peptide nanocomplexes (APN) were ca. 35 nm in size, stable at physiological pH and ionic strength, and retained in vitro antiviral activity against HCV and HIV. Moreover, incorporation of the peptide into APN attenuated its cytotoxicity associated with the positive charge. In vivo APN were able to decrease the viral load in mice transplanted with human lymphocytes and HIV-1-infected. Overall, these findings indicate the potential of these formulations for stabilization and delivery of antiviral peptides while maintaining their functional activity.

| S-EPMC3602242 | biostudies-literature

Allosteric disulfides: Sophisticated molecular structures enabling flexible protein regulation.

Project description:Protein disulfide bonds link pairs of cysteine residues in polypeptide chains. Many of these bonds serve a purely structural or energetic role, but a growing subset of cleavable disulfide bonds has been shown to control the function of the mature protein in which they reside. These allosteric disulfides and the factors that cleave these bonds are being identified across biological systems and life forms and have been shown to control hemostasis, the immune response, and viral infection in mammals. The discovery of these functional disulfides and a rationale for their facile nature has been aided by the emergence of a conformational signature for allosteric bonds. This post-translational modification mostly occurs extracellularly, making these chemical events prime drug targets. Indeed, a membrane-impermeable inhibitor of one of the cleaving factors is currently being trialed as an antithrombotic agent in cancer patients. Allosteric disulfides are firmly established as a sophisticated means by which a protein's shape and function can be altered; however, the full scope of this biological regulation will not be realized without new tools and techniques to study this regulation and innovative ways of targeting it.

| S-EPMC6393624 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data