Urea Transporters Identified as Novel Diuretic Drug Targets

2020 ◽  
Vol 21 (3) ◽  
pp. 279-287 ◽  
Author(s):  
Min Li ◽  
Shun Zhang ◽  
Baoxue Yang
Keyword(s):  
Small Molecule ◽  
Drug Targets ◽  
Renal Tubule ◽  
Electrolyte Imbalance ◽  
Electrolyte Balance ◽  
Urea Transporter ◽  
Small Molecule Drug ◽  
Compound Libraries ◽  
Vasa Recta ◽  
Urine Concentrating Ability

Background: Urea Transporters are a family of membrane channel proteins that facilitate the passive transport of urea across the plasma membrane. UTs are divided into two subgroups, UT-A and UT-B. UT-As are primarily located in renal tubule epithelia and UT-Bs are highly expressed in renal descending vasa recta and extrarenal multiple tissues. Various urea transporter knockout mice exhibit low urine concentrating ability, which suggests that UTs are novel diuretic targets. With highthroughput screening of small molecule drug-like compound libraries, various potent UT inhibitors with IC50 at nanomolar level were identified. Furthermore, selective UT inhibitors exhibit diuretic activity without disturbing electrolyte and metabolism balance, which confirms the potential of UTs as diuretic targets and UT inhibitors as novel diuretics that do not cause electrolyte imbalance. Objective: This review article summarizes the identification and validation of urea transporter as a potential diuretic target and the discovery of small molecule UT inhibitors as a novel type of diuretics. Conclusion: UTs are a potential diuretic target. UT inhibitors play significant diuresis and can be developed to diuretics without disturbing electrolyte balance.

scholarly journals Host Directed Therapies for Tuberculous Meningitis

2020 ◽  
Vol 5 ◽  
pp. 292
Author(s):  
Angharad G Davis ◽  
Joseph Donovan ◽  
Marise Bremer ◽  
Ronald Van Toorn ◽  
Johan Schoeman ◽  
...  
Keyword(s):  
Immune Response ◽  
Clinical Outcomes ◽  
Small Molecule ◽  
Tuberculous Meningitis ◽  
Drug Targets ◽  
Immunomodulatory Drugs ◽  
Small Molecule Drug ◽  
New Knowledge ◽  
Repurposed Drugs ◽  
Proven Benefit

A dysregulated host immune response significantly contributes to morbidity and mortality in tuberculous meningitis (TBM). Effective host directed therapies (HDTs) are critical to improve survival and clinical outcomes. Currently only one HDT, dexamethasone, is proven to improve mortality. However, there is no evidence dexamethasone reduces morbidity, how it reduces mortality is uncertain, and it has no proven benefit in HIV co-infected individuals. Further research on these aspects of its use, as well as alternative HDTs such as aspirin, thalidomide and other immunomodulatory drugs is needed. Based on new knowledge from pathogenesis studies, repurposed therapeutics which act upon small molecule drug targets may also have a role in TBM. Here we review existing literature investigating HDTs in TBM, and propose new rationale for the use of novel and repurposed drugs. We also discuss host variable responses and evidence to support a personalised approach to HDTs in TBM.

scholarly journals An Online Repository of Solvation Thermodynamic and Structural Maps of SARS-CoV-2 Targets

2020 ◽  
Author(s):  
Brian Olson ◽  
Anthony Cruz ◽  
Lieyang Chen ◽  
Mossa Ghattas ◽  
Yeonji Ji ◽  
...  
Keyword(s):  
Small Molecule ◽  
Drug Targets ◽  
Effective Vaccine ◽  
Mapping Data ◽  
Site Analysis ◽  
Small Molecule Drug ◽  
Small Molecule Drugs ◽  
Resultant Data ◽  
Severity Of The Disease ◽  
Solvation Theory

SARS-CoV-2 recently jumped species and rapidly spread via human-to-human transmission to cause a global outbreak of COVID-19. The lack of effective vaccine combined with the severity of the disease necessitates attempts to develop small molecule drugs to combat the virus. COVID19_GIST_HSA is a freely available online repository to provide solvation thermodynamic maps of COVID-19-related protein small molecule drug targets. Grid Inhomogeneous Solvation Theory maps were generated using AmberTools cpptraj-GIST and Hydration Site Analysis maps were created using SSTmap code. The resultant data can be applied to drug design efforts: scoring solvent displacement for docking, rational lead modification, prioritization of ligand- and protein- based pharmacophore elements, and creation of water-based pharmacophores. Herein, we demonstrate the use of the solvation thermodynamic mapping data. It is hoped that this freely provided data will aid in small molecule drug discovery efforts to defeat SARS-CoV-2.

Application of Biological Target Fishing Technology in Drug Discovery

2020 ◽  
Vol 980 ◽  
pp. 210-219
Author(s):  
Xian Zhi Ye
Keyword(s):  
Drug Discovery ◽  
Small Molecule ◽  
Drug Targets ◽  
Surface Plasma Resonance ◽  
Practical Applications ◽  
Small Molecule Drug ◽  
New Methods ◽  
Small Molecule Drugs ◽  
Biological Target ◽  
Target Fishing

Target fishing, a cutting-edge technology for drug research and development, plays a significant role in drug discovery. Varieties of methods for finding small-molecule drug targets have come into being driven by genomics, proteomics, bioinformatics and other technologies. These new methods are mainly based on the expression of gene or protein and proteins properties, including affinity and stability and so on. A serious challenge for the most widely used small molecule drugs is the discovery and identification of biological (and potential therapeutic) targets. Herein, we enumerate five biological target fishing techniques, including surface plasma resonance (SPR) techniques, random photo modified probes, drug affinity responsive target stability, fishing-rod strategy, and photo affinity labeling. And then we introduces the principles of operation, practical applications in the biological field of five methods, and analysis of their shortcomings.

Strategies to identify ligands for orphan G-protein-coupled receptors

2002 ◽  
Vol 30 (4) ◽  
pp. 789-793 ◽  
Author(s):  
G. Milligan
Keyword(s):  
Drug Design ◽  
G Protein ◽  
Small Molecule ◽  
Drug Targets ◽  
G Protein Coupled Receptors ◽  
Orphan Receptors ◽  
Protein Targets ◽  
Small Molecule Drug ◽  
Natural Ligands ◽  
G Protein Coupled

G-protein-coupled receptors are the most tractable class of protein targets for small molecule drug design. Sequencing of the human genome allied to bio-informatic analysis has identified a large number of putative receptors for which the natural ligands remain undefined. A range of currently employed and developing strategies to identify ligands that interact with these orphan receptors and to validate them as drug targets are described and discussed.

scholarly journals Host Directed Therapies for Tuberculous Meningitis

2021 ◽  
Vol 5 ◽  
pp. 292
Author(s):  
Angharad G. Davis ◽  
Joseph Donovan ◽  
Marise Bremer ◽  
Ronald Van Toorn ◽  
Johan Schoeman ◽  
...  
Keyword(s):  
Immune Response ◽  
Clinical Outcomes ◽  
Small Molecule ◽  
Tuberculous Meningitis ◽  
Drug Targets ◽  
Immunomodulatory Drugs ◽  
Small Molecule Drug ◽  
New Knowledge ◽  
Repurposed Drugs ◽  
Proven Benefit

A dysregulated host immune response significantly contributes to morbidity and mortality in tuberculous meningitis (TBM). Effective host directed therapies (HDTs) are critical to improve survival and clinical outcomes. Currently only one HDT, dexamethasone, is proven to improve mortality. However, there is no evidence dexamethasone reduces morbidity, how it reduces mortality is uncertain, and it has no proven benefit in HIV co-infected individuals. Further research on these aspects of its use, as well as alternative HDTs such as aspirin, thalidomide and other immunomodulatory drugs is needed. Based on new knowledge from pathogenesis studies, repurposed therapeutics which act upon small molecule drug targets may also have a role in TBM. Here we review existing literature investigating HDTs in TBM, and propose new rationale for the use of novel and repurposed drugs. We also discuss host variable responses and evidence to support a personalised approach to HDTs in TBM.

scholarly journals An Online Repository of Solvation Thermodynamic and Structural Maps of SARS-CoV-2 Targets

2020 ◽  
Author(s):  
Brian Olson ◽  
Anthony Cruz ◽  
Lieyang Chen ◽  
Mossa Ghattas ◽  
Yeonji Ji ◽  
...  
Keyword(s):  
Small Molecule ◽  
Drug Targets ◽  
Effective Vaccine ◽  
Mapping Data ◽  
Site Analysis ◽  
Small Molecule Drug ◽  
Small Molecule Drugs ◽  
Resultant Data ◽  
Severity Of The Disease ◽  
Solvation Theory

SARS-CoV-2 recently jumped species and rapidly spread via human-to-human transmission to cause a global outbreak of COVID-19. The lack of effective vaccine combined with the severity of the disease necessitates attempts to develop small molecule drugs to combat the virus. COVID19_GIST_HSA is a freely available online repository to provide solvation thermodynamic maps of COVID-19-related protein small molecule drug targets. Grid Inhomogeneous Solvation Theory maps were generated using AmberTools cpptraj-GIST and Hydration Site Analysis maps were created using SSTmap code. The resultant data can be applied to drug design efforts: scoring solvent displacement for docking, rational lead modification, prioritization of ligand- and protein- based pharmacophore elements, and creation of water-based pharmacophores. Herein, we demonstrate the use of the solvation thermodynamic mapping data. It is hoped that this freely provided data will aid in small molecule drug discovery efforts to defeat SARS-CoV-2.

scholarly journals Regulation of Renal Urea Transporters

1999 ◽  
Vol 10 (3) ◽  
pp. 635-646
Author(s):  
JEFF M. SANDS
Keyword(s):  
Apical Membrane ◽  
Collecting Duct ◽  
Basolateral Membrane ◽  
Molecular Evidence ◽  
Urea Transport ◽  
Urea Transporter ◽  
Transporter Family ◽  
Vasa Recta ◽  
Urea Reabsorption ◽  
Urine Concentrating Ability

Abstract. Urea is important for the conservation of body water due to its role in the production of concentrated urine in the renal inner medulla. Physiologic data demonstrate that urea is transported by facilitated and by active urea transporter proteins. The facilitated urea transporter (UT-A) in the terminal inner medullary collecting duct (IMCD) permits very high rates of transepithelial urea transport and results in the delivery of large amounts of urea into the deepest portions of the inner medulla where it is needed to maintain a high interstitial osmolality for concentrating the urine maximally. Four isoforms of the UT-A urea transporter family have been cloned to date. The facilitated urea transporter (UT-B) in erythrocytes permits these cells to lose urea rapidly as they traverse the ascending vasa recta, thereby preventing loss of urea from the medulla and decreasing urine-concentrating ability by decreasing the efficiency of countercurrent exchange, as occurs in Jk null individuals (who lack Kidd antigen). In addition to these facilitated urea transporters, three sodium-dependent, secondary active urea transport mechanisms have been characterized functionally in IMCD subsegments: (1) active urea reabsorption in the apical membrane of initial IMCD from low-protein fed or hypercalcemic rats; (2) active urea reabsorption in the basolateral membrane of initial IMCD from furosemide-treated rats; and (3) active urea secretion in the apical membrane of terminal IMCD from untreated rats. This review focuses on the physiologic, biophysical, and molecular evidence for facilitated and active urea transporters, and integrative studies of their acute and long-term regulation in rats with reduced urine-concentrating ability.

Characterization and Preclinical Perspectives of Organic Small Molecule Drug Metabolites in Drug-drug Interactions

2016 ◽  
Vol 20 (17) ◽  
pp. 1827-1834
Author(s):  
Liqian Gao ◽  
Jun Chen ◽  
Yi Hu ◽  
Hongyan Sun ◽  
Yong Siang Ong ◽  
...  
Keyword(s):  
Drug Interactions ◽  
Small Molecule ◽  
Drug Metabolites ◽  
Small Molecule Drug

Targeted Protein Degradation: "The Gold Rush is On!"

2020 ◽  
Vol 7 (1) ◽  
pp. 4-16
Author(s):  
Daria Kotlarek ◽  
Agata Pawlik ◽  
Maria Sagan ◽  
Marta Sowała ◽  
Alina Zawiślak-Architek ◽  
...  
Keyword(s):  
Drug Discovery ◽  
Protein Degradation ◽  
Small Molecule ◽  
Gold Rush ◽  
European Company ◽  
Drug Candidates ◽  
Protein Inhibition ◽  
Small Molecule Drug ◽  
Therapeutic Benefits ◽  
Talent Pool

Targeted Protein Degradation (TPD) is an emerging new modality of drug discovery that offers unprecedented therapeutic benefits over traditional protein inhibition. Most importantly, TPD unlocks the untapped pool of the proteome that to date has been considered undruggable. Captor Therapeutics (Captor) is the fourth global, and first European, company that develops small molecule drug candidates based on the principles of targeted protein degradation. Captor is located in Basel, Switzerland and Wroclaw, Poland and exploits the best opportunities of the two sites – experience and non-dilutive European grants, and talent pool, respectively. Through over $38 M of funding, Captor has been active in three areas of TPD: molecular glues, bi-specific degraders and direct degraders, ObteronsTM.

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