Design, synthesis and evaluation of inhibitors of voltage-gated sodium and proton channels : research data underlying the doctoral dissertation

Piga, Martina (author), Zidar, Nace (mentor), Tomašič, Tihomir (comentor)

The role that voltage-gated sodium and proton channels (NaV and HV1, respectively) play in neurotransmission, muscle contraction and immune response positions them in the midst of various physiological and pathological processes and makes them highly attractive pharmacological targets. However, the development of selective inhibitors is challenging due to high sequence similarity between different subtypes, which often leads to undesirable off-target effects. Additionally, suboptimal physicochemical and pharmacokinetic properties often limit their potential for in vivo efficacy. The aim of this doctoral dissertation was to overcome these limitations by developing novel inhibitors for voltage-gated sodium and proton channels with a favourable selectivity profile and improved drug-like properties. Our work specifically focused on NaV1.3 and NaV1.7 channels and their involvement in chronic neuropathic pain and on the role of hHV1 channels in tumour growth and progression. Two series of aryl sulphonamide-based hNaV1.3 inhibitors have been developed, yielding new chemical probes that offer great potential for further optimization and for elucidating the importance of the channel in the pathophysiology of pain. Ligand-based pharmacophore models based on known NaV1.7 inhibitors have been developed and validated, providing novel computational tools to accelerate NaV1.7 drug discovery. Finally, using computational methods, we have identified and subsequently optimized a new structural class of inhibitors of human HV1 channels and demonstrated their anticancer potential. Overall, we have demonstrated that our integrated approach, which combines computer-aided drug design with novel synthetic routes and pharmacological and biophysical profiling, can contribute to successfully overcome inherent challenges in voltage-gated ion channel drug discovery. The doctoral dissertation has contributed to a deeper understanding of voltage-gated ion channel pathophysiology and has facilitated the identification of novel voltage-gated ion channel inhibitors, providing a solid starting point for further research in the field of human NaV and HV1 modulators.

• Language: English
• Keywords: voltage-gated ion channels, NaV, HV1, inhibitor, 5-phenyl-2-aminoimidazole, aryl sulphonamide, virtual screening, anticancer, selectivity
• Typology: 2.20 - Complete scientific database of research data
• Organization: FFA - Faculty of Pharmacy
• Year: 2025
• PID: 20.500.12556/RUL-175026
• Data col. methods: Experiment: Laboratory
• Publication date in RUL: 17.10.2025

Licences

• License: CC BY 4.0, Creative Commons Attribution 4.0 International
• Link: http://creativecommons.org/licenses/by/4.0/
• Description: This is the standard Creative Commons license that gives others maximum freedom to do what they want with the work as long as they credit the author.
• Licensing start date: 14.10.2025
• Applies to: collected data

Secondary language

• Language: Slovenian
• Title: Načrtovanje, sinteza in vrednotenje zaviralcev napetostno odvisnih natrijevih in protonskih kanalčkov : raziskovalni podatki, obravnavani v doktorskem delu

Abstract

Pomembna vloga, ki jo imajo napetostno odvisni natrijevi in protonski kanali (NaV in HV1) pri živčnem prenosu, mišičnem krčenju in imunskem odzivu, jih postavlja v osrednji položaj pri številnih fizioloških in patoloških procesih, zaradi česar predstavljajo zelo perspektivne farmakološke tarče. Zaradi visoke stopnje podobnosti v aminokislinskem zaporedju med različnimi podtipi pa je razvoj selektivnih zaviralcev zahteven, kar pogosto vodi do neželenih učinkov. Poleg tega njihove neugodne fizikalno-kemijske in farmakokinetične lastnosti pogosto omejujejo njihovo učinkovitost in vivo. Namen doktorskega dela je bil preseči te omejitve z razvojem novih zaviralcev napetostno odvisnih natrijevih in protonskih kanalov z ugodnejšim profilom selektivnosti in izboljšanimi lastnostmi, ključnimi za zdravilne učinkovine. V okviru našega dela smo se zlasti osredotočili na kanala NaV1.3 in NaV1.7 ter na njuno vlogo pri kronični nevropatski bolečini ter na kanal hHV1 in njegov pomen pri rasti in napredovanju tumorjev. Razvili smo dve seriji arilsulfonamidnih zaviralcev hNaV1.3, ki predstavljajo nove kemične sonde za študij pomena teh kanalov v patofiziologiji bolečine, z velikim potencialom za nadaljnjo optimizacijo. Na osnovi znanih zaviralcev NaV1.7 smo razvili in validirali farmakoforne modele, ki predstavljajo nova računalniška orodja za hitrejše odkrivanje zdravilnih učinkovin z delovanjem na NaV1.7. Nazadnje smo z uporabo računalniško podprtih metod identificirali in optimizirali nov strukturni razred zaviralcev človeških kanalov HV1 ter dokazali njihov protirakav potencial. Na splošno smo pokazali, da lahko pristop, ki združuje računalniško podprto načrtovanje učinkovin z razvojem novih sinteznih poti ter farmakološkim in biofizikalnim vrednotenjem, uspešno prispeva k premagovanju temeljnih izzivov pri odkrivanju učinkovin z delovanjem na napetostno odvisne ionske kanale. Doktorska disertacija prispeva k boljšemu razumevanju patofiziologije napetostno odvisnih ionskih kanalov ter omogoča identifikacijo novih zaviralcev napetostno odvisnih ionskih kanalov. Naši rezultati predstavljajo dobro izhodišče za nadaljnje raziskave na področju zaviralcev človeških NaV in HV1 kanalov.

• Keywords: napetostno odvisni ionski kanali, NaV, HV1, zaviralec, 5-fenil-2-aminoimidazol, aril sulfonamid, virtualno rešetanje, protirakavo delovanje, selektivnost

Projects

• Funder: ARIS - Slovenian Research and Innovation Agency
• Project number: P1-0208
• Name: Farmacevtska kemija: načrtovanje, sinteza in vrednotenje učinkovin

• Funder: ARIS - Slovenian Research and Innovation Agency
• Funding programme: Young researchers