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Finding a Target
Published in Nathan Keighley, Miraculous Medicines and the Chemistry of Drug Design, 2020
In order to maximise intermolecular binding interactions, the receptor protein changes conformation to accommodate the chemical message. This change of shape in the receptor induces a cellular response to the signal. It is therefore clear that to design a drug that targets a specific receptor, it must satisfy these non-covalent interactions and partake in complementary binding. Essentially, the drug must mimic the natural substrate in an analogous way to enzyme-substrate complex formation. Moreover, given that cellular receptors control biochemical processes within the cell, drugs can be designed that either enhance or suppress cellular activities. Drugs that are designed to closely mimic the natural substrate are agonists; they have the effect of increasing the concentration of chemical messages so that the receptor is more frequently activated and the biochemical process to which that receptor is linked will be enhanced. In some instances, a drug may be required to supress the activity of the cell: antagonists are designed to mimic the natural substrate closely enough to interact with the receptor, but are sufficiently different as to not trigger a response upon binding. This has the effect of decreasing the availability of receptors and suppress the activity.
Regulation of Airway Smooth Muscle Proliferation by β2-Adrenoceptor Agonists
Published in Alastair G. Stewart, AIRWAY WALL REMODELLING in ASTHMA, 2020
Alastair G. Stewart, Paul R. Tomlinson, Leslie Schachte
Short-term exposure to β2-adrenoceptor agonists leads to a rapid desensitisation involving receptor sequestration. Longer-term exposure causes a decrease in receptor expression, referred to as downregulation, resulting from a decrease in the total amount of receptor protein.
Vagal Receptor Transport
Published in Sue Ritter, Robert C. Ritter, Charles D. Barnes, Neuroanatomy and Physiology of Abdominal Vagal Afferents, 2020
Finally, while the function of anterograde receptor transport is clear, the role of retrograde transport is not. Receptors can only be synthesized in the cell body and must be transported to their site of membrane incorporation. Laduron13,14 has suggested a number of potential roles for retrograde receptor transport from the periphery to the cell body. One role is to provide some recycling of the amino acid components of the receptor protein complex. This may take place either as recycling via the Golgi apparatus or degradation after fusion of lysosomes. The rate at which the retrograde transport and recycling of the components occurs may in some way play an important role in receptor regulation. For example, the synthesis of new receptor proteins may depend upon the rate at which recycled receptor components are returned to the cell body. The presence of these components may serve as a signal for receptor synthesis.
A randomized, double-blind, single-dose, single-center, parallel phase I clinical study comparing the pharmacokinetics, immunogenicity, safety, and tolerance of pertuzumab injection and Perjeta® in healthy Chinese male subjects
Published in Expert Opinion on Biological Therapy, 2022
Guangwen Liu, Zhongnan Xu, Wei Yang, Jinling Xue, Yanli Wang, Zhengzhi Liu, Yingzi Cui, Xinyao Qu, Tianying Chang, Shuang Yu, Yang Cheng, Yannan Zhou, Jiahui Chen, Qing Ren, Wanhua Wang, Qiaohuan Deng, Zeyu Wang, Haimiao Yang
Breast cancer is the most common cancer among women worldwide. It is also one of the leading causes of cancer-related death [1]. Breast cancer has become the leading cause of global cancer incidence in 2020, with an estimated 2.3 million new cases, representing 11.7% of all cancer cases [2]. Human epidermal growth factor receptor (HER2) is overexpressed in approximately 15–20% of diagnosed breast cancers [3]. HER2-positive breast cancer is one of the important factors of poor prognosis [3,4]. HER is a group of receptor proteins with similar structures and tyrosine kinase activity, including HER1, HER2, HER3, and HER4 [3]. After ligand binding, the receptor protein forms a homodimer or heterodimer [5], activates the tyrosine kinase, undergoes autophosphorylation, and changes local configuration, initiating corresponding physiological responses by intracellular signal transduction pathways [6].
The preventative effect of of Ro5-4864 (peripheral benzodiazepine receptor agonist) on spinal epidural fibrosis after laminectomy in a rat model
Published in Neurological Research, 2021
Emrah Keskin, Emine Yılmaz Can, Hasan Ali Aydın, Emre Işık, Utku Özgen, Kenan Şimşek, Osman Cengil, Cansu Başar, Murat Kalaycı
Nod-like receptor protein 3 (NLRP3) is found in the cytoplasm of immune system cells such as macrophages and microglia [43]. For the activation of this cytosolic receptor protein, which is involved in the initiation of inflammatory responses, danger signal associated with pathogens or damage must first reach the immune cell. As a result, IL-1β and IL-18, which are active forms of pro-IL-1β and pro-IL-18, are produced through NLRP3-mediated caspase-1 activation, while, at the same time, cell death is induced by this signal [43,44]. IL-1β, on the other hand, causes inflammation and ultimately fibrosis by increasing the release of reactive oxygen radicals and growth factors via neutrophils. There are many studies in the literature indicating a direct relationship between NLRP3 inflammasome and fibrosis (Figure 4) [45–48]. Lee et al. demonstrated, for the first time, that Ro5-4864 inhibited ATP-induced mitochondrial damage in monocyte and macrophage cells, resulting in the inhibition of NLRP3 inflammasome activation [49]. However, there is no study in the literature showing the relationship between NLRP3 inflammasome and EF. We consider that the results of our study will guide future studies on EF.
A patent review of adaptor associated kinase 1 (AAK1) inhibitors (2013-present)
Published in Expert Opinion on Therapeutic Patents, 2021
Belén Martinez-Gualda, Dominique Schols, Steven De Jonghe
Kinases are a heavily explored drug target class in academic laboratories as well as in the pharmaceutical industry. This cumulated in the approval, by the US Food and Drug Administration (FDA), of 65 small-molecule kinase inhibitors [52]. Although the human kinome contains more than 500 kinases, current drug discovery efforts focus only on a small subset of the kinome. Of the 65 kinase inhibitors that received marketing approval, 37 inhibit receptor protein tyrosine kinases, 13 inhibit non-receptor protein-tyrosine kinases, 11 are directed at protein-serine/threonine protein kinases and 4 are dual specificity protein kinase inhibitors. Since several of these drugs are multikinase inhibitors, these kinases should be considered as their primary or intended target. However, a large fraction of the kinome, known as the ‘dark kinome’, has not been explored yet. In addition, the majority of kinase inhibitors are profiled in oncology settings, with other therapeutic domains lagging behind, although a limited number of kinase inhibitors has been licensed for the treatment of (auto)immune diseases and to prevent graft rejection after organ transplantation.