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Rask-Andersen, Mathias, et al.
(författare)
Advances in kinase targeting : current clinical use and clinical trials
2014
Ingår i: TIPS - Trends in Pharmacological Sciences. - : Elsevier BV. - 0165-6147 .- 1873-3735. ; 35:11, s. 60-76
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.
3.
Karlsson, Oskar, et al.
(författare)
Imaging mass spectrometry in drug development and toxicology
2017
Ingår i: Archives of Toxicology. - : Springer Science and Business Media LLC. - 0340-5761 .- 1432-0738. ; 91:6, s. 2283-2294
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.
4.
Albofetileh, Mehdi, et al.
(författare)
Seaweed Proteins as a Source of Bioactive Peptides
2021
Ingår i: Current Pharmaceutical Design. - : Bentham Science Publishers Ltd.. - 1873-4286 .- 1381-6128. ; 27:11, s. 1342 -1352
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.
5.
Fleming, Cassandra L., et al.
(författare)
On-Command Regulation of Kinase Activity using Photonic Stimuli
2019
Ingår i: ChemPhotoChem. - : Wiley. - 2367-0932. ; 3:6, s. 318-326
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.
6.
El-Seedi, Hesham R., et al.
(författare)
Recent insights into the biosynthesis and biological activities of natural xanthones
2010
Ingår i: Current Medicinal Chemistry. - : Bentham Science Publishers Ltd.. - 0929-8673 .- 1875-533X. ; 17:9, s. 854-901
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.
7.
Marshall, Garland R, et al.
(författare)
Limiting Assumptions in the Design of Peptidomimetics
2017
Ingår i: Drug development research. - : Wiley. - 0272-4391 .- 1098-2299. ; 78:6, s. 245-267
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.
8.
Andersson, Karl-Erik
(författare)
Detrusor contraction - Focus on muscarinic receptors
2004
Ingår i: Scandinavian Journal of Urology and Nephrology. - : Informa UK Limited. - 0036-5599 .- 1651-2065. ; 38:Suppl 215, s. 54-57
Forskningsöversikt (refereegranskat) abstract
Stimulation of muscarinic receptors is a main mechanism for contractile activation of the detrusor from both animals and humans. Muscarinic receptors are coupled to G-proteins, but the signal transduction systems may vary. In general, M-1 , M-3 and M-5 receptors are considered to couple preferentially to G(q/11) , activating phosphoinositide hydrolysis, in turn leading to mobilization of intracellular calcium through inositol trisphosphate generation. M-2 and M-4 receptors couple to pertussis toxin-sensitive G(i/o) , resulting in inhibition of adenylyl cyclase activity. However, in the detrusor smooth muscle, other signalling pathways may be involved. Recent investigations revealed that a main pathway for muscarinic receptor activation of the detrusor may be calcium influx via L-type calcium channels, and increased sensitivity to calcium of the contractile machinery via inhibition of myosin light chain phosphatase through activation of Rho-kinase. The importance of these findings for treatment of voiding dysfunction remains to be established.
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