Interpretable bilinear attention network with domain adaptation improves drug–target prediction

Peizhen Bai, Filip Miljković, Bino John & Haiping Lu

Abstract

Predicting drug–target interaction is key for drug discovery. Recent deep learning-based methods show promising performance, but two challenges remain: how to explicitly model and learn local interactions between drugs and targets for better prediction and interpretation and how to optimize generalization performance of predictions on novel drug–target pairs. Here, we present DrugBAN, a deep bilinear attention network (BAN) framework with domain adaptation to explicitly learn pairwise local interactions between drugs and targets, and adapt in response to out-of-distribution data. DrugBAN works on drug molecular graphs and target protein sequences to perform prediction, with conditional domain adversarial learning to align learned interaction representations across different distributions for better generalization on novel drug–target pairs. Experiments on three benchmark datasets under both in-domain and cross-domain settings show that DrugBAN achieves the best overall performance against five state-of-the-art baseline models. Moreover, visualizing the learned bilinear attention map provides interpretable insights from prediction results.

Borneol exerts its antipruritic effects by inhibiting TRPA1 and activating TRPM8

Miao Luoa,1, Jinfeng Hea,1, Liang Yina, Ping Zhanb, Zhongqiu Zhaoc, Hui Xionga,d,**, Zhinan Meia,e,*

a School of Pharmaceutical Sciences, South-Central Minzu University, Wuhan, 430074, China
b Dermatology Hospital of Jiangxi Province, Nanchang, 330000, China
c Barnes-Jewish Hospital, St. Louis, MO, 63110, USA
d Ethnopharmacology Level 3 Laboratory of National Administration of Traditional Chinese Medicine, South-Central Minzu University, Wuhan, 430074, China e College of Plant Science and Technology, Huazhong Agricultural University, Wuhan, 430070, China

Ethnopharmacological relevance: Borneol is a long-established traditional Chinese medicine that has been found to be effective in treating pain and itchy skin. However, whether borneol has a therapeutic effect on chronic itch and its related mechanisms remain unclear.
Aim of the study: To investigate the antipruritic effect of borneol and its molecular mechanism.

Materials and methods: DrugBAN framework and molecular docking were applied to predict the targets of borneol, and the calcium imaging or patch-clamp recording analysis were used to detect the effects of borneol on TRPA1, TRPM8 or TRPV3 channels in HEK293T cells. In addition, various mouse models of acute itch and chronic itch were established to evaluate the antipruritic effects of borneol on C57BL/6J mice. Then, the borneol- induced pruritic relief was further investigated in Trpa1− /− , Trpm8− /− , or Trpa1− /− /Trpm8− /− mice. The effects of borneol on the activation of TRPM8 and the inhibition of TRPA1 were also measured in dorsal root ganglia neurons of wild-type (WT), Trpm8− /− and Trpv1− /− mice. Lastly, a randomized, double-blind study of adult patients was conducted to evaluate the clinical antipruritic effect of borneol.

Results: TRPA1, TRPV3 and TRPM8 are the potential targets of borneol according to the results of DrugBAN algorithm and molecular docking. Calcium imaging and patch-clamp recording analysis demonstrated that borneol activates TRPM8 channel-induced cell excitability and inhibits TRPA1 channel-mediated cell excitability in transfected HEK293T cells. Animal behavior analysis showed that borneol can significantly reduce acute and chronic itch behavior in C57BL/6J mice, but this effect was eliminated in Trpa1− /− , Trpm8− /− mice, or at least in Trpa1− /− /Trpm8− /− mice. Borneol elicits TRPM8 channel induced [Ca2+]i responses but inhibits AITC or SADBE- induced activation of TRPA1 channels in dorsal root ganglia neurons of WT and Trpv1− /− mice, respectively. Furthermore, the clinical results indicated that borneol could reduce itching symptoms in patients and its efficacy is similar to that of menthol.

Conclusion: Borneol has therapeutic effects on multiple pruritus models in mice and patients with chronic itch, and the mechanism may be through inhibiting TRPA1 and activating TRPM8.

S. aureus drives itch and scratch-induced skin damage through a V8 protease-PAR1 axis -2

Abstract

Itch is an unpleasant sensation that evokes a desire to scratch. The skin barrier is constantly exposed to microbes and their products. However, the role of microbes in itch generation is unknown. Here, we show that Staphylococcus aureus, a bacterial pathogen associated with itchy skin diseases, directly activates pruriceptor sensory neurons to drive itch. Epicutaneous S. aureus exposure causes robust itch and scratch-induced damage. By testing multiple isogenic bacterial mutants for virulence factors, we identify the S. aureus serine protease V8 as a critical mediator in evoking spontaneous itch and alloknesis. V8 cleaves proteinase-activated receptor 1 (PAR1) on mouse and human sensory neurons. Targeting PAR1 through genetic deficiency, small interfering RNA (siRNA) knockdown, or pharmacological blockade decreases itch and skin damage caused by V8 and S. aureus exposure. Thus, we identify a mechanism of action for a pruritogenic bacterial factor and demonstrate the potential of inhibiting V8-PAR1 signaling to treat itch.

Presenter: Ju Hee Ryu

S. aureus drives itch and scratch-induced skin damage through a V8 protease-PAR1 axis -1

Abstract

Itch is an unpleasant sensation that evokes a desire to scratch. The skin barrier is constantly exposed to microbes and their products. However, the role of microbes in itch generation is unknown. Here, we show that Staphylococcus aureus, a bacterial pathogen associated with itchy skin diseases, directly activates pruriceptor sensory neurons to drive itch. Epicutaneous S. aureus exposure causes robust itch and scratch-induced damage. By testing multiple isogenic bacterial mutants for virulence factors, we identify the S. aureus serine protease V8 as a critical mediator in evoking spontaneous itch and alloknesis. V8 cleaves proteinase-activated receptor 1 (PAR1) on mouse and human sensory neurons. Targeting PAR1 through genetic deficiency, small interfering RNA (siRNA) knockdown, or pharmacological blockade decreases itch and skin damage caused by V8 and S. aureus exposure. Thus, we identify a mechanism of action for a pruritogenic bacterial factor and demonstrate the potential of inhibiting V8-PAR1 signaling to treat itch.

Presenter: Ji Eun Cha

Molecular mechanisms of MrgprA3-independent activation of the transient receptor potential ion channels TRPA1 andTRPV1 by chloroquine

Tabea C Fricke ¹, Sebastian Pantke ¹, Bjarne Lüttmann ¹, Frank G Echtermeyer ¹, Christine Herzog ¹, Mirjam J Eberhardt ¹, Andreas Leffler ¹

Affiliations expand

• PMID: 36928865
• DOI: 10.1111/bph.16072

Abstract

Background and purpose: Itch is associated with several pathologies and is a common drug-induced side effect. Chloroquine (CQ) is reported to induce itch by activating the Mas-related G protein-coupled receptor MrgprA3 and subsequently TRPA1. In this study, we demonstrate that CQ employs at least two MrgprA3-independent mechanisms to activate or sensitize TRPA1 and TRPV1.

Experimental approach: Patch clamp and calcium imaging were utilized to examine effects of CQ on TRPA1 and TRPV1 expressed in HEK 293T cells.

Key results: In calcium imaging, CQ induces a concentration-dependent but MrgprA3-independent activation of TRPA1 and TRPV1. Although CQ itself inhibits TRPA1 and TRPV1 in patch clamp recordings, co-application of CQ and ultraviolet A (UVA) light evokes membrane currents through both channels. This effect is inhibited by the reducing agent dithiothreitol (DTT) and is reduced on mutants lacking cysteine residues accounting for reactive oxygen species (ROS) sensitivity. The combination of CQ and UVA light triggers an accumulation of intracellular ROS, removes fast inactivation of voltage-gated sodium currents and activates TRPV2. On the other hand, CQ is a weak base and induces intracellular alkalosis. Intracellular alkalosis can activate TRPA1 and TRPV1, and CQ applied at alkaline pH values indeed activates both channels.

Conclusion and implications: Our data reveal novel pharmacological properties of CQ, allowing activation of TRPA1 and TRPV1 via photosensitization as well as intracellular alkalosis. These findings add more complexity to the commonly accepted dogma that CQ-induced itch is specifically mediated by MrgprA3 coupling to TRPA1.

Keywords: chloroquine; histamine; itch; oxidative stress; sensory neuron.

© 2023 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.

Cav3.2 T-type calcium channel mediates acute itch and contributes to chronic itch and inflammation in experimental atopic dermatitis

Ji-Woong Ahn ¹, Song-Ee Kim ², Do-Young Kim ³, Inhye Jeong ², Sohyun Kim ¹, Seungsoo Chung ⁴, Sang Eun Lee ⁵

• PMID: 37863387
• DOI: 10.1016/j.jid.2023.07.029

Abstract

Voltage-gated calcium channels regulate neuronal excitability. The Cav3.2 isoform of the T-type voltage-activated calcium channel is expressed in sensory neurons and is implicated in pain transmission. However, its role in itch remains unclear. Herein, we demonstrated that Cav3.2 is expressed by mechanosensory and peptidergic subsets of mouse dorsal root ganglion (DRG) neurons and colocalized with TRPV1 and receptors for type 2 cytokines. Cav3.2-positive neurons innervate human skin. A deficiency of Cav3.2 reduces histamine, IL-4/IL-13, and thymic stromal lymphopoietin-induced itch in mice. Cav3.2 channels were upregulated in the DRGs of an atopic dermatitis (AD)-like mouse model and mediated neuronal excitability. Genetic knockout of Cav3.2 or T-type calcium channel blocker mibefradil treatment reduced spontaneous and mechanically induced scratching behaviors and skin inflammation in an AD-like mouse model. Substance P and vasoactive intestinal polypeptide levels were increased in the trigeminal ganglia (TG) from AD-like mouse model, and genetic ablation or pharmacological inhibition of Cav3.2 reduced their gene expression. Cav3.2 knockout also attenuated the pathologic changes in ex vivo skin explants co-cultured with TG neurons from AD-induced mice. Our study identifies the role of Cav3.2 in both histaminergic and non-histaminergic acute itch. Cav3.2 channel also contributes to AD-related chronic itch and neuroinflammation.

Keywords: Cav3.2; T-type voltage-activated calcium channel; atopic dermatitis; itch; neuroinflammation; substance P; vasoactive intestinal polypeptide.

Pain and itch coding mechanisms of polymodal sensory neurons

Abstract

Pain and itch coding mechanisms in polymodal sensory neurons remain elusive. MrgprD+ neurons represent a major polymodal population and mediate both mechanical pain and nonhistaminergic itch. Here, we show that chemogenetic activation of MrgprD+ neurons elicited both pain- and itch-related behavior in a dose-dependent manner, revealing an unanticipated compatibility between pain and itch in polymodal neurons. While VGlut2-dependent glutamate release is required for both pain and itch transmission from MrgprD+ neurons, the neuropeptide neuromedin B (NMB) is selectively required for itch signaling. Electrophysiological recordings further demonstrated that glutamate synergizes with NMB to excite NMB-sensitive postsynaptic neurons. Ablation of these spinal neurons selectively abolished itch signals from MrgprD+ neurons, without affecting pain signals, suggesting a dedicated itch-processing central circuit. These findings reveal distinct neurotransmitters and neural circuit requirements for pain and itch signaling from MrgprD+ polymodal sensory neurons, providing new insights on coding and processing of pain and itch.

Presenter: Ju Hee Ryu

Satellite Glial Cells and Neurons in Trigeminal Ganglia Are Altered in an Itch Model in Mice

MeytalCohen1,2, RachelFeldman-Goriachnik1,2 and MenachemHanani1,2,*

1 LaboratoryofExperimentalSurgery,Hadassah-HebrewUniversityMedicalCenter,Jerusalem91240,Israel; meytal.cohen@mail.huji.ac.il(M.C.);rahel.gor@gmail.com(R.F.-G.)

2 FacultyofMedicine,TheHebrewUniversityofJerusalem,MountScopus,Jerusalem91240,Israel * Correspondence:hananim@cc.huji.ac.il;Tel.:+972-2-5844721

Abstract: Itch(pruritus) is a common chronic condition with a lifetime prevalence of over 20%. The mechanisms underlying itch are poorly understood,and its therapy is difficult. There is recent evidence that following nerve injury or inflammation, intercellular communications in sensory ganglia are augmented, which may lead to abnormal neuronal activity, and hence to pain, but there is no information on whether such changes take place in an itch model. We studied changes in neurons and satellite glial cells(SGCs)in trigeminal ganglia in an itch model in mice using repeated applications of 2,4,6-trinitro-1-chlorobenzene(TNCB) to the external ear over a period of 11days. Treated mice showed augmented scratching behavior as compared with controls during the application period and for several days afterward.Immunostaining for the activation marker glial fibrillary acidic protein SGCs was greater by about 35% after TNCB application, and gap junction-mediated coupling between neurons increased from about 2% to 13%. The injection of gap junction blockers reduced scratching behavior, suggesting that gap junctions contribute to itch. Calcium imaging studies showed increased responses of SGCs to the pain (and presumed itch )mediator ATP. We conclude that changes in both neurons and SGCs in sensory ganglia may play a role in itch.