Identification of pharmacological chaperones as potential therapeutic agents to treat phenylketonuria.
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ABSTRACT:
SUBMITTER: Pey AL
PROVIDER: S-EPMC2441854 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Missense mutations in the lysosomal hydrolase ?-galactocerebrosidase (GALC) account for at least 40% of known cases of Krabbe disease (KD). Most of these missense mutations are predicted to disrupt the fold of the enzyme, preventing GALC in sufficient amounts from reaching its site of action in the lysosome. The predominant central nervous system (CNS) pathology and the absence of accumulated primary substrate within the lysosome mean that strategies used to treat other lysosomal storage disorders (LSDs) are insufficient in KD, highlighting the still unmet clinical requirement for successful KD therapeutics. Pharmacological chaperone therapy (PCT) is one strategy being explored to overcome defects in GALC caused by missense mutations. In recent studies, several small-molecule inhibitors have been identified as promising chaperone candidates for GALC. This Review discusses new insights gained from these studies and highlights the importance of characterizing both the chaperone interaction and the underlying mutation to define properly a responsive population and to improve the translation of existing lead molecules into successful KD therapeutics. We also highlight the importance of using multiple complementary methods to monitor PCT effectiveness. Finally, we explore the exciting potential of using combination therapy to ameliorate disease through the use of PCT with existing therapies or with more generalized therapeutics, such as proteasomal inhibition, that have been shown to have synergistic effects in other LSDs. This, alongside advances in CNS delivery of recombinant enzyme and targeted rational drug design, provides a promising outlook for the development of KD therapeutics. © 2016 The Authors. Journal of Neuroscience Research Published by Wiley Periodicals, Inc.
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Project description:Methylmalonic aciduria (MMA) cblB type is caused by mutations in the MMAB gene. This encodes the enzyme ATP:cob(I)alamin adenosyltransferase (ATR), which converts reduced cob(I)alamin to an active adenosylcobalamin cofactor. We recently reported the presence of destabilizing pathogenic mutations that retain some residual ATR activity. The aim of the present study was to seek pharmacological chaperones as a tailored therapy for stabilizing the ATR protein. High-throughput ligand screening of over 2000 compounds was performed; six were found to enhance the thermal stability of purified recombinant ATR. Further studies using a well-established bacterial system in which the recombinant ATR protein was expressed in the presence of these six compounds, showed them all to increase the stability of the wild-type ATR and the p.Ile96Thr mutant proteins. Compound V (N-{[(4-chlorophenyl)carbamothioyl]amino}-2-phenylacetamide) significantly increased this stability and did not act as an inhibitor of the purified protein. Importantly, compound V increased the activity of ATR in patient-derived fibroblasts harboring the destabilizing p.Ile96Thr mutation in a hemizygous state to within control range. When cobalamin was coadministrated with compound V, mutant ATR activity further improved. Oral administration of low doses of compound V to C57BL/6J mice for 12 days, led to increase in steady-state levels of ATR protein in liver and brain (disease-relevant organs). These results hold promise for the clinical use of pharmacological chaperones in MMA cblB type patients harboring chaperone-responsive mutations.
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Project description:Coronaviruses are pleomorphic, enveloped, or spherical viruses, which have a size ranging from 80 to 120 nm. These viruses act on receptors that cause the triggering of fusion. Coronaviruses were first described after cultivation from patients with common colds by Tyrell and Bynoe in 1966. There are various subtypes of coronavirus, 7 out of these can cause infection in human beings. The Alpha subtype is responsible for mild infection showing symptoms or infection without any prevailing symptoms. On the other hand, the beta subtype is responsible for very serious diseases leading to fatality. The lineage of this novel SARS-CoV-2 falls under the beta lineage of the beta coronavirus which has been observed to have a relation to the MERS and SARS coronavirus. In the Huanan market selling seafood, the transition of this novel virus in humans from animals has occurred. It has the potential to be the cause of widespread fatality amongst the people of the globe. On August 16, 2020, the World Health Organisation had reported 2,1294,845 cases which are confirmed to date out of which 413,372 deaths have occurred. Currently, no targeted antiviral vaccines or drugs to fight against COVID-19 infection have been approved for use in humans. This pandemic is fast emerging and drug repurposing is the only ray of hope which can ensure quick availability. Vaccine development is progressing each day with various platforms such as DNA, Live Attenuated Virus, Non-Replicating Viral Vector, Protein Subunit, and RNA, being utilized for the development. COVID-19 attacks the immune system of the host & this can result in a cytokine storm. As a result, various herbal agents both acting as antivirals and immunomodulatory can also be used. Convalescent Plasma Therapy and Mesenchymal Stem Cell therapy are also being explored as a plausible therapeutic. There remains a considerable unmet need for therapeutics to be addressed. The development and availability of accessible and efficient therapy are essential for the treatment of patients. This review discusses the epidemiology, pathogenesis, the tale of origin, and transmission of COVID-19 or Sars-Cov2 virus and gives evidence of potential therapeutic agents that can be explored to cast away this pandemic.
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Project description:As the coronavirus disease 2019 (COVID-19, also called severe acute respiratory syndrome coronavirus-2) outbreak accelerates, vigorous and diverse efforts were made in developing treatment strategies. In addition to direct acting agents, increasing evidence showed some potential adjuvant therapies with promising efficacy against COVID-19. These therapies include immunomodulators (i.e. intravenous immunoglobulin, thymosin α-1, interleukin [IL]-6, tocilizumab, cyclosporine, thalidomide, fingolimod), Chinese medicines (i.e. glycyrrhizin, baicalin, Xuebijing), anti-vascular endothelial growth factors (bevacizumab), estrogen modulating drugs, statins, and nutritional supplements (i.e. vitamins A, B, C, D, E and zinc). This article reviewed the pharmacological development of potential adjuvants for COVID-19 treatment.
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Project description:The term "pharmacological chaperone" was introduced 20 years ago. Since then the approach with this type of drug has been proposed for several diseases, lysosomal storage disorders representing the most popular targets. The hallmark of a pharmacological chaperone is its ability to bind a protein specifically and stabilize it. This property can be beneficial for curing diseases that are associated with protein mutants that are intrinsically active but unstable. The total activity of the affected proteins in the cell is lower than normal because they are cleared by the quality control system. Although most pharmacological chaperones are reversible competitive inhibitors or antagonists of their target proteins, the inhibitory activity is neither required nor desirable. This issue is well documented by specific examples among which those concerning Fabry disease. Direct specific binding is not the only mechanism by which small molecules can rescue mutant proteins in the cell. These drugs and the properly defined pharmacological chaperones can work together with different and possibly synergistic modes of action to revert a disease phenotype caused by an unstable protein.
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Project description:Coronavirus disease 2019 (COVID-19), the seventh human coronavirus infectious disease, was first reported in Wuhan, China, in December 2019, followed by its rapid spread globally (251,059 deaths, on May 5, 2020, by Johns Hopkins University). An early clinical report showed that fever, cough, fatigue, sputum production, and myalgia were initial symptoms, with the development of pneumonia as the disease progressed. Increases in the level of serum liver enzymes, D-dimer, cardiac troponin I, and creatinine have been observed in severely ill patients, indicating that multiple organ failure had occurred in these cases. Lymphopenia and an increase in interleukin-6 (IL-6) were also observed. Although COVID-19 patients are administered glucocorticoid therapy to treat the excessive immune response to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection, the efficacy of this form of therapy is unclear. Viremia is observed in severe cases, suggesting that in addition to type II alveolar epithelial cells, many cell types, such as vascular endothelial cells, cardiomyocytes, renal tubular cells, neuronal cells, and lymphocytes, may be damaged. The improvement of survival rates requires elucidation of the mechanism by which cellular damage occurs during viral infection. Cellular therapy, along with organ support systems such as oxygen therapy, artificial ventilation, extra corporeal membrane oxygenation and dialysis, as well as antiviral therapy, are required. Viral replication in infected host cells may perturb protein folding in the endoplasmic reticulum (ER), causing ER stress. Although an adaptive cellular response, i.e. the unfolded protein response, can compensate for the misfolded protein burden to some extent, continued viral proliferation may induce inflammation and cell death. Therefore, we propose that proteostasis dysfunction may cause conformational disorders in COVID-19. The application of pharmacological chaperone therapy to treat COVID-19 patients is additionally discussed.
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Project description:Galactosemia is a rare inherited metabolic disease resulting from mutations in the four genes which encode enzymes involved in the metabolism of galactose. The current therapy, the removal of galactose from the diet, is inadequate. Consequently, many patients suffer lifelong physical and cognitive disability. The phenotype varies from almost asymptomatic to life-threatening disability. The fundamental biochemical cause of the disease is a decrease in enzymatic activity due to failure of the affected protein to fold and/or function correctly. Many novel therapies have been proposed for the treatment of galactosemia. Often, these are designed to treat the symptoms and not the fundamental cause. Pharmacological chaperones (PC) (small molecules which correct the folding of misfolded proteins) represent an exciting potential therapy for galactosemia. In theory, they would restore enzyme function, thus preventing downstream pathological consequences. In practice, no PCs have been identified for potential application in galactosemia. Here, we review the biochemical basis of the disease, identify opportunities for the application of PCs and describe how these might be discovered. We will conclude by considering some of the clinical issues which will affect the future use of PCs in the treatment of galactosemia.
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Project description:The unforeseen emergence of coronavirus disease 2019 (COVID-19), a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) at the Wuhan province of China in December 2019, subsequently its abrupt spread across the world has severely affected human life. In a short span of time, COVID-19 has sacked more than one million human lives and marked as a severe global pandemic, which is drastically accountable for the adverse effect directly to the human society, particularly the health care system and the economy. The unavailability of approved and effective drugs or vaccines against COVID-19 further created conditions more adverse and terrifying. To win the war against this pandemic within time there is a desperate need for the most adequate therapeutic treatment, which can be achieved by the collaborative research work among scientists worldwide. In continuation of our efforts to support the scientific community, a review has been presented which discusses the structure and the activity of numerous molecules exhibiting promising SARS-CoV-2 and other CoVs inhibition activities. Furthermore, this review offers an overview of the structure, a plausible mechanism of action of SARS-CoV-2, and crucial structural features substantial to inhibit the primary virus-based and host-based targets involved in SARS-CoV-2 treatment. We anticipate optimistically that this perspective will provide the reader and researcher's better understanding regarding COVID-19 and pave the path in the direction of COVID-19 drug discovery and development paradigm.
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Project description:The efficacy of superoxide dismutase-1 (SOD1) folding impacts neuronal loss in motor system neurodegenerative diseases. Mutations can prevent SOD1 post-translational processing leading to misfolding and cytoplasmic aggregation in familial amyotrophic lateral sclerosis (ALS). Evidence of immature, wild-type SOD1 misfolding has also been observed in sporadic ALS, non-SOD1 familial ALS and Parkinson's disease. The copper chaperone for SOD1 (hCCS) is a dedicated and specific chaperone that assists SOD1 folding and maturation to produce the active enzyme. Misfolded or misfolding prone SOD1 also interacts with heat shock proteins and macrophage migration inhibitory factor to aid folding, refolding or degradation. Recognition of specific SOD1 structures by the molecular chaperone network and timely dissociation of SOD1-chaperone complexes are, therefore, important steps in SOD1 processing. Harnessing these interactions for therapeutic benefit is actively pursued as is the modulation of SOD1 behaviour with pharmacological and peptide chaperones. This review highlights the structural and mechanistic aspects of a selection of SOD1-chaperone interactions together with their impact on disease models.
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