Host-directed therapies (HDTs) that modulate host-pathogen interactions offer an innovative strategy to combat Mycobacterium tuberculosis (Mtb) infections. When combined with tuberculosis (TB)... Show moreHost-directed therapies (HDTs) that modulate host-pathogen interactions offer an innovative strategy to combat Mycobacterium tuberculosis (Mtb) infections. When combined with tuberculosis (TB) antibiotics, HDTs could contribute to improving treatment outcomes, reducing treatment duration, and preventing resistance development. Translation of the interplay of host-pathogen interactions leveraged by HDTs towards therapeutic outcomes in patients is challenging. Quantitative understanding of the multifaceted nature of the host-pathogen interactions is vital to rationally design HDT strategies. Here, we (i) provide an overview of key Mtb host-pathogen interactions as basis for HDT strategies; and (ii) discuss the components and utility of quantitative systems pharmacology (QSP) models to inform HDT strategies. QSP models can be used to identify and optimize treatment targets, to facilitate preclinical to human translation, and to design combination treatment strategies. Show less
Solute carrier transporters (SLCs) limit receptor activation via uptake of extracellular ligands. Novel concepts are emerging that describe the modulation of intracellular and plasma membrane... Show moreSolute carrier transporters (SLCs) limit receptor activation via uptake of extracellular ligands. Novel concepts are emerging that describe the modulation of intracellular and plasma membrane receptors by ligand influx and efflux via SLCs, respectively. Here, we evaluate recent insights and provide an outlook for developing potential therapeutic strategies. Show less
Mehta, K.M.; Spaink, H.P.; Ottenhoff, T.H.M.; Graaf, P.H. van der; Hasselt, J.G.C. van 2021
Host-directed therapies (HDTs) that modulate host-pathogen interactions offer an innovative strategy to combat Mycobacterium tuberculosis (Mtb) infections. When combined with tuberculosis (TB)... Show moreHost-directed therapies (HDTs) that modulate host-pathogen interactions offer an innovative strategy to combat Mycobacterium tuberculosis (Mtb) infections. When combined with tuberculosis (TB) antibiotics, HDTs could contribute to improving treatment outcomes, reducing treatment duration, and preventing resistance development. Translation of the interplay of host-pathogen interactions leveraged by HDTs towards therapeutic outcomes in patients is challenging. Quantitative understanding of the multifaceted nature of the host-pathogen interactions is vital to rationally design HDT strategies. Here, we (i) provide an overview of key Mtb host-pathogen interactions as basis for HDT strategies; and (ii) discuss the components and utility of quantitative systems pharmacology (QSP) models to inform HDT strategies. QSP models can be used to identify and optimize treatment targets, to facilitate preclinical to human translation, and to design combination treatment strategies. Show less
The chemokine system, comprising 48 chemokines and 23 receptors, is critically involved in several hallmarks of cancer. Yet, despite extensive efforts from the pharmaceutical sector, only two drugs... Show moreThe chemokine system, comprising 48 chemokines and 23 receptors, is critically involved in several hallmarks of cancer. Yet, despite extensive efforts from the pharmaceutical sector, only two drugs aimed at this system are currently approved for clinical use against cancer. To date, numerous pharmacological approaches have been developed to successfully intervene at different stages of chemokine function: (i) chemokine availability; (ii) chemokine-glycosaminoglycan binding; and (iii) chemokine receptor binding. Many of these strategies have been tested in preclinical cancer models, and some have advanced to clinical trials as potential anticancer therapies. Here we will review the strategies and growing pharmacological toolbox for manipulating the chemokine system in cancer, and address novel methods poised for future (pre)clinical testing. Show less
Recent crystal structures of multiple G protein-coupled receptors (GPCRs) have revealed a highly conserved intracellular pocket that can be used to modulate these receptors from the inside. This... Show moreRecent crystal structures of multiple G protein-coupled receptors (GPCRs) have revealed a highly conserved intracellular pocket that can be used to modulate these receptors from the inside. This novel intracellular site partially overlaps with the G protein and β-arrestin binding site, providing a new manner of pharmacological intervention. Here we provide an update of the architecture and function of the intracellular region of GPCRs, until now portrayed as the signaling domain. We review the available evidence on the presence of intracellular binding sites among chemokine receptors and other class A GPCRs, as well as different strategies to target it, including small molecules, pepducins, and nanobodies. Finally, the potential advantages of intracellular (allosteric) ligands over orthosteric ligands are also discussed. Show less
TrendsRecent technological advances in membrane protein crystallization have resulted in a nearly exponential increase of available receptor structures. The AR family is an important example in... Show moreTrendsRecent technological advances in membrane protein crystallization have resulted in a nearly exponential increase of available receptor structures. The AR family is an important example in this respect. Crystal structures of antagonist- and agonist-bound adenosine A2A receptor have recently been supplemented by a fully activated conformation in complex with a G-protein mimic, and by antagonist bound structures of the A1 receptor.SDM experiments have been essential to identify residues involved in molecular interactions between ARs and their ligands. Leveraging on recent crystal structures, this vast amount of data can now be systematically classified and interconnected with chemical and structural information of ligands and receptors.The mapping of mutational data onto crystal structures provides new understanding of molecular interactions involved in ligand recognition. Together with computational modeling, this can be used as a roadmap to create novel hypotheses and assist in the design of more systematic mutagenesis studies to answer remaining structural and functional questions.The four adenosine receptors (ARs), A1, A2A, A2B, and A3, constitute a subfamily of G protein-coupled receptors (GPCRs) with exceptional foundations for structure-based ligand design. The vast amount of mutagenesis data, accumulated in the literature since the 1990s, has been recently supplemented with structural information, currently consisting of several inactive and active structures of the A2A and inactive conformations of the A1 ARs. We provide the first integrated view of the pharmacological, biochemical, and structural data available for this receptor family, by mapping onto the relevant crystal structures all site-directed mutagenesis data, curated and deposited at the GPCR database (available through http://www.gpcrdb.org). This analysis provides novel insights into ligand binding, allosteric modulation, and signaling of the AR family.Keywords: G protein-coupled receptor, adenosine receptor, mutagenesis, chemical modulationShow less
Currently, the clinical utility of taxane-based drug formulations in castration-resistant prostate cancer (CRPC) is severely limited by acquired chemotherapy resistance, dose-limiting toxicities,... Show moreCurrently, the clinical utility of taxane-based drug formulations in castration-resistant prostate cancer (CRPC) is severely limited by acquired chemotherapy resistance, dose-limiting toxicities, and nonresponders. Therefore, approaches to improve taxane-based chemotherapy are desperately required. In this review, we highlight the strategies that aim to overcome these limitations, such as bypassing therapy resistance, targeted drug delivery, and adequate prediction of therapy response. The involvement of the apoptotic pathway, ABC transporters, the glucocorticoid receptor (GR) axis, androgen receptor (AR) splicing, epithelial plasticity, and cancer stem cells in mediating taxane-resistance are outlined. Furthermore, passive and active targeted nanomedicinal drug delivery strategies and the use of circulating tumor cells in predicting docetaxel responses are discussed. Finally, recent advances towards clinical translation of these approaches in CRPC are reviewed. Show less
