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| 2. |
- Karlsson, Oskar, et al.
(författare)
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Imaging mass spectrometry in drug development and toxicology
- 2017
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Ingår i: Archives of Toxicology. - : Springer Science and Business Media LLC. - 0340-5761 .- 1432-0738. ; 91:6, s. 2283-2294
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Forskningsöversikt (refereegranskat)abstract
- During the last decades, imaging mass spectrometry has gained significant relevance in biomedical research. Recent advances in imaging mass spectrometry have paved the way for in situ studies on drug development, metabolism and toxicology. In contrast to whole-body autoradiography that images the localization of radiolabeled compounds, imaging mass spectrometry provides the possibility to simultaneously determine the discrete tissue distribution of the parent compound and its metabolites. In addition, imaging mass spectrometry features high molecular specificity and allows comprehensive, multiplexed detection and localization of hundreds of proteins, peptides and lipids directly in tissues. Toxicologists traditionally screen for adverse findings by histopathological examination. However, studies of the molecular and cellular processes underpinning toxicological and pathologic findings induced by candidate drugs or toxins are important to reach a mechanistic understanding and an effective risk assessment strategy. One of IMS strengths is the ability to directly overlay the molecular information from the mass spectrometric analysis with the tissue section and allow correlative comparisons of molecular and histologic information. Imaging mass spectrometry could therefore be a powerful tool for omics profiling of pharmacological/toxicological effects of drug candidates and toxicants in discrete tissue regions. The aim of the present review is to provide an overview of imaging mass spectrometry, with particular focus on MALDI imaging mass spectrometry, and its use in drug development and toxicology in general.
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| 3. |
- Tavella, T A, et al.
(författare)
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Yeast-based high-throughput screens for discovery of kinase inhibitors for neglected diseases.
- 2021
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Ingår i: Advances in Protein Chemistry and Structural Biology. - : Elsevier. - 1876-1631. ; 124, s. 275-309
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Forskningsöversikt (refereegranskat)abstract
- The discovery and development of a new drug is a complex, time consuming and costly process that typically takes over 10 years and costs around 1 billion dollars from bench to market. This scenario makes the discovery of novel drugs targeting neglected tropical diseases (NTDs), which afflict in particular people in low-income countries, prohibitive. Despite the intensive use of High-Throughput Screening (HTS) in the past decades, the speed with which new drugs come to the market has remained constant, generating doubts about the efficacy of this approach. Here we review a few of the yeast-based high-throughput approaches that can work synergistically with parasite-based, in vitro, or in silico methods to identify and optimize novel antiparasitic compounds. These yeast-based methods range from HTP screens to identify novel hits against promising parasite kinase targets to the identification of potential antiparasitic kinase inhibitors extracted from databases of yeast chemical genetic screens.
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| 4. |
- Albofetileh, Mehdi, et al.
(författare)
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Seaweed Proteins as a Source of Bioactive Peptides
- 2021
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Ingår i: Current Pharmaceutical Design. - : Bentham Science Publishers Ltd.. - 1873-4286 .- 1381-6128. ; 27:11, s. 1342 -1352
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Forskningsöversikt (refereegranskat)abstract
- Seaweeds have gained great attention as a vegetarian and sustainable marine source of protein which do not need irrigation, arable land and fertilization. Besides, seaweeds are considered as an untapped resource for discovering bioactive compounds with health benefits where bioactive peptides have shown outstanding potential. This review provides a detailed overview of available scientific knowledge on production methods, bioactivity and application of peptides from seaweed proteins. The emphasize is on the effects form seaweed varieties and peptide production condition on the bioactivity of the peptides and their potential health benefits. Bioactive properties of seaweed peptides including antioxidant, antihypertensive, antidiabetic, anti-inflammatory, anticancer activities and other potential health benefits have been discussed. It also covers current challenges and required future research and innovations for the successful application of seaweeds proteins as a sustainable source of bioactive peptides. Effects from seasonal variation of seaweed composition on the bioactivity of their peptides, difficulties in the extraction of proteins from seaweed complex structure, scalability and reproducibility of the developed methods for the production of bioactive peptides, the safety of the peptides are examples of highlighted challenges. Further studies on the bioavailability of the seaweed bioactive peptides and validation of the results in animal models and human trials are needed before their application as functional foods or pharmaceutical ingredients.
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| 5. |
- Rask-Andersen, Mathias, et al.
(författare)
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Advances in kinase targeting : current clinical use and clinical trials
- 2014
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Ingår i: TIPS - Trends in Pharmacological Sciences. - : Elsevier BV. - 0165-6147 .- 1873-3735. ; 35:11, s. 60-76
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Forskningsöversikt (refereegranskat)abstract
- Phosphotransferases, also known as kinases, are the most intensively studied protein drug target category in current pharmacological research, as evidenced by the vast number of kinase-targeting agents enrolled in active clinical trials. This development has emerged following the great success of small-molecule, orally available protein kinase inhibitors for the treatment of cancer, starting with the introduction of imatinib (Gleevec (R)) in 2003. The pharmacological utility of kinase-targeting has expanded to include treatment of inflammatory diseases, and rapid development is ongoing for kinase-targeted therapies in a broad array of indications in ophthalmology, analgesia, central nervous system (CNS) disorders, and the complications of diabetes, osteoporosis, and otology. In this review we highlight specifically the kinase drug targets and kinase-targeting agents being explored in current clinical trials. This analysis is based on a recent estimate of all established and clinical trial drug mechanisms of action, utilizing private and public databases to create an extensive dataset detailing aspects of more than 3000 approved and experimental drugs.
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| 6. |
- Grubb, A
(författare)
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Diagnostic value of analysis of cystatin C and protein HC in biological fluids
- 1992
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Ingår i: Clinical Nephrology. - 0301-0430. ; 38:Suppl 1, s. 20-527
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Forskningsöversikt (refereegranskat)abstract
- Cystatin C, a 13 kDa-protein, is produced by most nucleated cells and is catabolized by the renal tubular cells after passing the glomerular filter. It belongs to the family 2 of the cystatin superfamily of proteins. The function of cystatin C is to regulate the activity of cysteine proteinases and cystatin C seems to be the main cysteine proteinase inhibitor of most investigated human biological fluids. Its normal level in plasma is 0.8-2.5 mg/l, in cerebrospinal fluid 4-14 mg/l and in urine 0.03-0.3 mg/l. The production rate of cystatin C is remarkably constant and its plasma concentration can therefore be used as a reliable measure of the glomerular filtration rate (GFR). Indeed, the cystatin C plasma concentration is more closely correlated to the GFR than the plasma levels of creatinine and all other investigated low molecular weight proteins, including beta 2-microglobulin and retinol binding protein. Protein HC, alias alpha 1-microglobulin, is produced by the liver as a 27 kDa-glycoprotein. It belongs to the lipocalin superfamily of hydrophobic ligand binding proteins and more than 50% of the normal plasma amount of protein HC is present as a high molecular weight HC-IgA complex carrying antibody activity. The plasma concentration of free protein HC is, in contrast to that of HC-IgA, mainly determined by the GFR. The normal values for the plasma concentrations of HC-IgA and free protein HC are 36-620 mg/l and 14-26 mg/l, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)
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| 7. |
- Fleming, Cassandra L., et al.
(författare)
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On-Command Regulation of Kinase Activity using Photonic Stimuli
- 2019
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Ingår i: ChemPhotoChem. - : Wiley. - 2367-0932. ; 3:6, s. 318-326
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Forskningsöversikt (refereegranskat)abstract
- The underlying role that many kinases play in complex cellular pathways as well as disease remains unclear. To better understand the role that kinases play in both health and disease states, the use of light as an external stimulus to modulate kinase activity with high spatiotemporal resolution has gained increasing interest over the years. Herein we highlight the progress made towards the development of light-responsive kinase enzymes and small molecule inhibitors. In these examples, photolabile caging groups and photoswitchable entities have been utilised to modulate either kinase activation or inhibition in a light-controlled manner.
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| 8. |
- El-Seedi, Hesham R., et al.
(författare)
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Recent insights into the biosynthesis and biological activities of natural xanthones
- 2010
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Ingår i: Current Medicinal Chemistry. - : Bentham Science Publishers Ltd.. - 0929-8673 .- 1875-533X. ; 17:9, s. 854-901
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Forskningsöversikt (refereegranskat)abstract
- This review focuses on recent advances in our understanding of the complex biosynthetic pathways and diverse biological activities of naturally occurring xanthones. The biosynthesis section covers studies published from 1989 to 2008 on xanthone production in plants and fungi, while the bioactivity review presents tabulated activities of more than 250 xanthones described in studies published from 2001 to 2008, together with structural information and indications of their wide-ranging potential uses as pharmacological tools. A large number of relevant papers have been published on these subjects (128 cited here), illustrating the diversity of the xanthones and their possible uses.
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| 9. |
- Marshall, Garland R, et al.
(författare)
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Limiting Assumptions in the Design of Peptidomimetics
- 2017
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Ingår i: Drug development research. - : Wiley. - 0272-4391 .- 1098-2299. ; 78:6, s. 245-267
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Forskningsöversikt (refereegranskat)abstract
- Limiting the flexibility of organic compounds to enhance their affinity and selectivity for targeting a macromolecule involved in molecular recognition has become a well-developed paradigm in medicinal chemistry. While the role of reverse-turn motifs as peptidomimetics has received the most attention, β-sheets and helices are also important motifs for protein/protein interactions. The more complicated problem of mimicking the interacting surface of noncontiguous epitopes will not be considered in this review. This limited overview focuses on efforts to use amino acid synthons as secondary-structure mimetics as well as providing examples of peptidomimetic design focused on nonpeptide synthetic chemistry in contrast. In particular, the rationale of optimal design criteria for mimicry and the many naïve violations of those criteria made in its pursuit are emphasized.
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| 10. |
- Daly, Norelle, et al.
(författare)
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Discovery, structure and biological activities of cyclotides
- 2009
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Ingår i: Advanced Drug Delivery Reviews. - : Advanced Drug Delivery Reviews. - 0169-409X .- 1872-8294. ; 61, s. 918-930
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Forskningsöversikt (övrigt vetenskapligt/konstnärligt)abstract
- Cyclotides are small disulfide-rich peptides that are characterized by a head-to-tail cyclized peptide backbone and a knotted arrangement of three conserved disulfide bonds. They are present in many plants from the Violaceae, Rubiaceae and Cucurbitaceae families, with individual plants expressing a suite of dozens of cyclotides. So far > 140 sequences and 15 three-dimensional structures have been determined but it is estimated that the family probably comprises many thousands of members. Their primary function in plants is thought to be as defense agents, based on their potent insecticidal activity, but they also have a range of other biological activities, including anti-HIV, antimicrobial and cytotoxic activities. Because of their exceptional stability they have attracted interest as templates for protein engineering and drug design applications. This article gives an overview of the discovery of cyclotides, describes their unique structural features and range of bioactivities, and discusses their applications in drug design.
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