scholarly journals Rational Design of a Modality‐Specific Inhibitor of TRPM8 Channel against Oxaliplatin‐Induced Cold Allodynia

2021 ◽  
pp. 2101717
Author(s):  
Aerziguli Aierken ◽  
Ya‐Kai Xie ◽  
Wenqi Dong ◽  
Abuliken Apaer ◽  
Jia‐Jia Lin ◽  
...  
Keyword(s):  
Rational Design ◽  
Specific Inhibitor ◽  
Trpm8 Channel ◽  
Cold Allodynia

scholarly journals Structure-based characterization of novel TRPV5 inhibitors

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
Taylor ET Hughes ◽  
John Smith Del Rosario ◽  
Abhijeet Kapoor ◽  
Aysenur Torun Yazici ◽  
Yevgen Yudin ◽  
...  
Keyword(s):  
Rational Design ◽  
Transient Receptor Potential ◽  
Trp Channels ◽  
Parent Compound ◽  
Specific Inhibitor ◽  
Receptor Potential ◽  
Selective Inhibition ◽  
Transient Receptor Potential Vanilloid ◽  
Calcium Reabsorption ◽  
Transient Receptor

Transient receptor potential vanilloid 5 (TRPV5) is a highly calcium selective ion channel that acts as the rate-limiting step of calcium reabsorption in the kidney. The lack of potent, specific modulators of TRPV5 has limited the ability to probe the contribution of TRPV5 in disease phenotypes such as hypercalcemia and nephrolithiasis. Here, we performed structure-based virtual screening (SBVS) at a previously identified TRPV5 inhibitor binding site coupled with electrophysiology screening and identified three novel inhibitors of TRPV5, one of which exhibits high affinity, and specificity for TRPV5 over other TRP channels, including its close homologue TRPV6. Cryo-electron microscopy of TRPV5 in the presence of the specific inhibitor and its parent compound revealed novel binding sites for this channel. Structural and functional analysis have allowed us to suggest a mechanism of action for the selective inhibition of TRPV5 and lay the groundwork for rational design of new classes of TRPV5 modulators.

scholarly journals Rational design of novel fluorescent enzyme biosensors for direct detection of strigolactones

2020 ◽  
Author(s):  
Rebecca J Chesterfield ◽  
Jason H Whitfield ◽  
Benjamin Pouvreau ◽  
Da Cao ◽  
Christine A Beveridge ◽  
...  
Keyword(s):  
High Throughput ◽  
High Throughput Screening ◽  
Rational Design ◽  
Direct Detection ◽  
Specific Inhibitor ◽  
Striga Hermonthica ◽  
Signalling Molecules ◽  
Domain Insertion

AbstractStrigolactones are plant hormones and rhizosphere signalling molecules with key roles in plant development, mycorrhizal fungal symbioses, and plant parasitism. Currently, sensitive, specific, and high-throughput methods of detecting strigolactones are limited. Here, we developed genetically encoded fluorescent strigolactone biosensors based on the strigolactone receptors DAD2 from Petunia hybrida, and HTL7 from Striga hermonthica via domain insertion of circularly permuted GFP. The DAD2 biosensor exhibited loss of cpGFP fluorescence in vitro upon treatment with the strigolactones 5-deoxystrigol and orobanchol, or the strigolactone analogue GR24. The biosensor likewise responded to strigolactones in an in vivo protoplast system, and retained strigolactone hydrolysis activity. The ShHTL7 biosensor exhibited loss of cpGFP fluorescence upon GR24 treatment in vitro, and responded to a specific inhibitor of ShHTL7 but not DAD2, indicating that the biosensors retained the specificity of their parent receptors. These biosensors have applications in high-throughput screening, and may also have utility for studying strigolactone biology.

scholarly journals Oxaliplatin Causes Transient Changes in TRPM8 Channel Activity

2021 ◽  
Vol 22 (9) ◽  
pp. 4962
Author(s):  
Vittoria Rimola ◽  
Tabea Osthues ◽  
Vanessa Königs ◽  
Gerd Geißlinger ◽  
Marco Sisignano
Keyword(s):  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Trpm8 Channel ◽  
Cold Allodynia ◽  
Transient Receptor Potential Melastatin ◽  
Oxaliplatin Treatment ◽  
Peripheral Pain ◽  
Transient Receptor ◽  
Underlying Mechanisms

Oxaliplatin is a third-generation platinum-based anticancer drug that is widely used as first-line treatment for colorectal carcinoma. Patients treated with oxaliplatin develop an acute peripheral pain several hours after treatment, mostly characterized by cold allodynia as well as a long-term chronic neuropathy. These two phenomena seem to be causally connected. However, the underlying mechanisms that trigger the acute peripheral pain are still poorly understood. Here we show that the activity of the transient receptor potential melastatin 8 (TRPM8) channel but not the activity of any other member of the TRP channel family is transiently increased 1 h after oxaliplatin treatment and decreased 24 h after oxaliplatin treatment. Mechanistically, this is connected with activation of the phospholipase C (PLC) pathway and depletion of phosphatidylinositol 4,5-bisphosphate (PIP2) after oxaliplatin treatment. Inhibition of the PLC pathway can reverse the decreased TRPM8 activity as well as the decreased PIP2-concentrations after oxaliplatin treatment. In summary, these results point out transient changes in TRPM8 activity early after oxaliplatin treatment and a later occurring TRPM8 channel desensitization in primary sensory neurons. These mechanisms may explain the transient cold allodynia after oxaliplatin treatment and highlight an important role of TRPM8 in oxaliplatin-induced acute and neuropathic pain.

Molecular insights on the dynamic stability of peptide nucleic acid functionalized carbon and boron nitride nanotubes

2021 ◽  
Vol 23 (1) ◽  
pp. 219-228
Author(s):  
Nabanita Saikia ◽  
Mohamed Taha ◽  
Ravindra Pandey
Keyword(s):  
Nucleic Acid ◽  
Boron Nitride ◽  
Nucleic Acids ◽  
Dynamic Stability ◽  
Peptide Nucleic Acid ◽  
Rational Design ◽  
Peptide Nucleic Acids ◽  
Boron Nitride Nanotubes ◽  
Molecular Hybrids ◽  
Single Wall Nanotubes

The rational design of self-assembled nanobio-molecular hybrids of peptide nucleic acids with single-wall nanotubes rely on understanding how biomolecules recognize and mediate intermolecular interactions with the nanomaterial's surface.

Optimizing electron density of nickel sulfide electrocatalysts through sulfur vacancy engineering for alkaline hydrogen evolution

2020 ◽  
Vol 8 (35) ◽  
pp. 18207-18214
Author(s):  
Dongbo Jia ◽  
Lili Han ◽  
Ying Li ◽  
Wenjun He ◽  
Caichi Liu ◽  
...  
Keyword(s):  
Hydrogen Evolution ◽  
Electron Density ◽  
Rational Design ◽  
Nickel Sulfide ◽  
Catalytic Performance ◽  
Sulfide Catalysts ◽  
Sulfur Vacancy

A novel, rational design for porous S-vacancy nickel sulfide catalysts with remarkable catalytic performance for alkaline HER.

Rational design of annotine analogues with increased inhibitory activity towards acetylcholinesterase

Planta Medica ◽  
2016 ◽  
Vol 81 (S 01) ◽  
pp. S1-S381
Author(s):  
ES Halldorsdottir ◽  
S Oddsson ◽  
AM Einarsdottir ◽  
B Eiriksdottir ◽  
NM Kowal ◽  
...  
Keyword(s):  
Inhibitory Activity ◽  
Rational Design

Platelet-Bound Prekallikrein Promotes Pro-Urokinase-Induced Clot Lysis: A Mechanism for Targeting the Factor XII Dependent Intrinsic Pathway of Fibrinolysis

1994 ◽  
Vol 71 (03) ◽  
pp. 347-352 ◽  
Author(s):  
Jean-Pierre Loza ◽  
Victor Gurewich ◽  
Michael Johnstone ◽  
Ralph Pannell
Keyword(s):  
Platelet Rich Plasma ◽  
Specific Inhibitor ◽  
Specific Effect ◽  
Clot Lysis ◽  
Factor Xii ◽  
Intrinsic Pathway ◽  
Clot Retraction ◽  
Enzymatic Mechanism ◽  
Low Concentrations ◽  
Factor Xiia

SummaryClots formed from platelet rich plasma were found to be lysed more readily by low concentrations of pro-urokinase (pro-UK) than clots formed from platelet poor plasma. This was not a non-specific effect since the reverse occurred with tissue plasminogen activator. A mechanical explanation due to platelet-mediated clot retraction was excluded by experiments in which retraction was inhibited with cyto-chalasin B. Therefore, a platelet-mediated enzymatic mechanism was postulated to explain the promotion of fibrinolysis. Casein autography of isolated platelets revealed a ≈ 90 kDa band of activity which comigrated with plasma prekallikrein (PK)/kallikrein, a known activator of pro-UK. Furthermore, treatment of platelets with plasma PK activator (PPA), consisting essentially of factor XIIa, induced activation of pro-UK and of chromomgenic substrate for kallikrein (S-2302). This activity corresponded to approximately 40-200 pM kallikrein per 10 8 washed and gel filtered platelets per ml. The activation of pro-UK by PPA-pretreated platelets was dose-dependent and inhibited by soybean trypsin inhibitor but not by bdellin, a specific inhibitor of plasmin, nor by the corn inhibitor of factor XIIa. Kinetic analysis of pro-UK activation by kallikrein showed promotion of the reaction by platelets. The KM of the reaction was reduced by platelets by ≈ 7-fold, while the kcat was essentially unchanged. In conclusion, PK was shown to be tightly associated with platelets where it can be activated by factor XIIa during clotting. The activation of pro-UK by platelet-bound kallikrein provides an explanation for the observed platelet mediated promotion of pro-UK-induced clot lysis. Since pro-UK and plasminogen have also been shown to be associated with platelets, the present findings suggest a mechanism by which the factor Xlla-dependent intrinsic pathway of fibrinolysis can be localized and targeted to a thrombus.

Anticoagulant Activity of Hirulog™, a Direct Thrombin Inhibitor, in Humans

1993 ◽  
Vol 69 (02) ◽  
pp. 157-163 ◽  
Author(s):  
Irving Fox ◽  
Adrian Dawson ◽  
Peter Loynds ◽  
Jane Eisner ◽  
Kathleen Findlen ◽  
...  
Keyword(s):  
Rational Design ◽  
Therapeutic Potential ◽  
Anticoagulant Activity ◽  
Subcutaneous Administration ◽  
Direct Thrombin Inhibitor ◽  
Controlled Study ◽  
Thrombin Inhibitor ◽  
Thrombin Time ◽  
Thrombotic Disease ◽  
Dose Dependent

SummaryHirulog™ (BG8967) is a direct thrombin inhibitor built by rational design using the protein hirudin as a model (Maraganore et al. [1990]; Biochemistry 29: 7095–101). In order to evaluate the therapeutic potential for hirulog in the management of thrombotic disease, the tolerability and anticoagulant activity of the agent were examined in a study of human volunteers.In a randomized, placebo-controlled study (n = 54), the intravenous infusion of hirulog over 15 min showed a rapid, dose-dependent prolongation of activated partial thromboplastin time (APTT), prothrombin time (PT), and thrombin time (TT). There was a corresponding dose-dependent increase in plasma hirulog levels. The peptide was rapidly cleared with a half-life of 36 min and a total body clearance rate for the peptide of 0.43 1 kg−1 h−1. Similar activity was observed following subcutaneous injection but with sustained pharmacodynamic and pharmacokinetic behavior. There was a significant correlation between pharmacokinetic and pharmacodynamic variables for both intravenous (r = 0.8, p <0.001) and subcutaneous administration (r = 0.7, p = 0.002).To evaluate the possible interactions of aspirin on the tolerability and anticoagulant activity of intravenous hirulog, a cross-over design was employed in eight subjects. Aspirin administration did not modify the peptide’s activity. At the administered dose of 0.6 mg kg−1 h−1 for 2 h, hirulog infusion prolonged APTT from 230 to 260% baseline. The infusion of hirulog in subjects who had received aspirin was not associated with any significant changes in the template bleeding time.The final phase of the study examined the activity and tolerability of hirulog in ten subjects during prolonged intravenous infusions for up to 24 h. The peptide (0.3 mg kg−1 h−1) exhibited sustained anticoagulant activity with no evidence for a cumulative effect. During hirulog infusion, APTT was prolonged from 210 to 250% baseline.In all phases of the study, hirulog administration was generally well-tolerated.Our observations show that hirulog is an active antithrombin agent with excellent tolerability in humans. As a direct thrombin inhibitor, hirulog provides a novel approach for the management of thrombotic disease.

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