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• W187607573 abstract "Chronic pain is responsible for great physical, mental and economic loss. While there are diverse methods available for managing pain, such as NSAID, opioids and local anesthetics, common issues associated such as addiction and tolerance highlights the unmet demand for a novel analgesic aimed at a novel target. Numerous reports on individuals suffering from loss of function mutations in SCN9A marker, which leads to complete inability to feel pain, yet otherwise normal physiology, has led to the recognition of voltage gated sodium channel 1.7 (NaV1.7) as a prime pain target. Other reports of gain of function mutations that lead to conditions such as paroxysmal extreme pain disorder and primary erythromelalgia confirms the validity of this target. However the presence of nine closely related subtypes of voltage gated sodium channels, NaV1.1-NaV1.9 introduces complications as any cross inhibition may lead to detrimental results. For example inhibition of NaV1.5 subtype could result in cardiac arrhythmia to complete cardiac arrest and death. Therefor it is of utmost importance that any pharmaceutical agent used to inhibit NaV1.7 is highly specific for NaV1.7 and display no cross reactivity on other voltage gated channels. Spiders are one of the most successful terrestrial predators; their venoms have evolved over many millions of years to selectively and potently inhibit nervous system targets in order to rapidly paralyze their prey. Spider-venom peptidomes have been identified as one of the largest known libraries of compounds with very high potency and specificity towards nervous system targets. Spider toxins listed in the Arachnoserver database have been classified into 12 families of sodium channel toxins (NaSpTx), denoted NaSpTx Families 1–12, based on the level of sequence conservation and intercystine spacing. NaSpTx family 2 is the largest toxin family; it comprises 34 peptides of theraphosid origin. This thesis primarily aims at discovering novel inhibitors of NaV1.7. However the intriguing fact that people suffering form congenital indifference to pain also suffers form anosmia, has lead to efforts of understanding the role of NaV1.7 in olfaction. This study has been completed with the finding that NaV1.7 is located along axons of olfactory neurones. These findings have been published and research article is attached as chapter 4. During the initial discovery phase of this project, an assay guided fractionation method was used to identify NaV1.7 inhibitors form six spider venoms. This resulted in nine fully sequenced peptides where four of these belonged to NaSpTx family 2. This included the well-known β/ω-TRTX-Tp1a (Protoxin1). Three novel peptides discovered were named β-TRTX-Pe1a, μ-TRTX-Pe1b, and U-TRTX-Pa1a. A complete alanine scan of β/ω-TRTX-Tp1a on NaV1.7 was conducted using a Xenopus laevis oocyte based tethered toxin method. Residues that were important for NaV1.7 binding were mapped onto the three-dimensional structure of β/ω-TRTX-Tp1a. Three novel toxin peptides β-TRTX-Pe1a, β/μ-TRTX-Pe1b, and U-TRTX-Pa1a were recombinantly expressed using an Escherichia coli (E. coli) based system. Channel modulating activities of these toxins were assessed using a Xenopus laevis oocyte based two-electrode voltage clamp system (TEVC). μ-TRTX-Pe1b demonstrated a high degree of selectivity for NaV1.7. It is about 20 times more selective over NaV1.2, which is abundant in the central nervous system, and appears to mildly potentate NaV1.5, which is the cardiac subtype. This is despite the complete set of active residues uncovered in β/ω-TRTX-Tp1a alanine scan being fully conserved in β/μ-TRTX-Pe1b. β-TRTX-Pe1a and U1-TRTX-Pa1a have shown very weak NaV1.7 inhibition, hence not investigated in great detail. The introduction of the mutation S35 to the sequence of β/μ-TRTX-Pe1b has resulted in the β/μ-TRTX-Pe1b-S35, which has shown increased NaV1.7 activity that is almost comparable to β/ω-TRTX-Tp1a. Structure activity relations (SAR) of β/ω-TRTX-Tp1a and β/μ-TRTX-Pe1b-S35 are currently under investigation. It is highly promising that better understanding of residues responsible for the high potency of β/ω-TRTX-Tp1a and higher NaV selectivity of β/μ-TRTX-Pe1b-S35 would lead to engineering a superior NaV1.7 inhibiting analgesic agent. This thesis has widened our understanding of NaSpTx family 2 peptides, and residues, which may be important in achieving NaV1.7 selectivity by inhibitor peptides." @default.
• W187607573 created "2016-06-24" @default.
• W187607573 creator A5039565878 @default.
• W187607573 date "2015-03-04" @default.
• W187607573 modified "2023-09-24" @default.
• W187607573 title "Developing novel analgesics to treat chronic pain: inhibiting voltage gated sodium channel 1.7 with spider-venom peptides" @default.
• W187607573 doi "https://doi.org/10.14264/uql.2015.346" @default.
• W187607573 hasPublicationYear "2015" @default.
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