Hi1a and ProTx-II
Hi1a (from Hadronyche infensa; the clinical candidate derived from it carries the code IB409); ProTx-II (protoxin-II, β-theraphotoxin-Tp1a, from Thrixopelma pruriens)
1What it is
These two peptides are the clearest illustration of how spider venom is used in drug discovery, and of why it so rarely arrives.
Hi1a comes from the venom of Hadronyche infensa, a funnel-web spider from K'gari (Fraser Island) in Queensland — a close relative of the Sydney funnel-web and a genuinely dangerous animal. Glenn King's group at the University of Queensland, screening venoms for ion channel activity, found that Hi1a inhibits ASIC1a with high potency and unusual selectivity. ASIC1a opens when extracellular pH falls, which is exactly what happens in tissue cut off from its blood supply, and the channel is a major contributor to the neuronal death that follows a stroke. Blocking it is therefore a candidate neuroprotective strategy — and the central problem in stroke medicine is that there is no drug that protects brain tissue while circulation is being restored. The reported ability of Hi1a to reduce infarct size in rats even when given hours after stroke onset is what made the finding notable, because that time window is the one that matters clinically.
The same logic applies to the heart. A Hi1a-derived candidate, IB409, entered a Phase 1 safety and tolerability trial in January 2026, aimed at reducing ischaemic injury in heart attack and stroke. Results are not available. This is a first-in-human safety study, not evidence of benefit.
ProTx-II comes from the Peruvian green velvet tarantula and inhibits Nav1.7. That target has about as strong a human genetic validation as any in analgesia: people with loss-of-function mutations in the gene encoding Nav1.7 are congenitally unable to feel pain while remaining otherwise largely normal. A selective Nav1.7 blocker should therefore be a powerful analgesic. ProTx-II blocks Nav1.7 potently — and has nonetheless failed as an analgesic for reasons that are instructive and are covered below. It remains a widely used laboratory probe for sodium channel work.
2How it's thought to work
Hi1a:
3What the research shows
Hi1a — neuroprotection in rodent stroke
Hi1a — cardioprotection
Hi1a — human data
ProTx-II — Nav1.7 pharmacology
ProTx-II — analgesia in animals
ProTx-II — human data
4Reported side effects and interactions
Literature-reported
Literature (Hi1a). no published human safety data; the Phase 1 trial is the first human exposure. In rodent work the peptide was reported to be well tolerated at neuroprotective doses. ASIC1a has physiological roles in fear conditioning, learning and synaptic plasticity, so sustained central blockade would be expected to have central effects; acute use in an emergency setting is a different proposition from chronic dosing, and is what the programme is aimed at.
Literature (ProTx-II). the dose-limiting toxicity in animals is cardiovascular and neuromuscular, consequent on incomplete selectivity against cardiac Nav1.5 and skeletal muscle Nav1.4 at systemic exposures. Reported effects include cardiovascular depression and motor impairment. This is the reason it is a reagent rather than a candidate.
Literature (envenomation). Hadronyche and Atrax funnel-web bites are medical emergencies in eastern Australia — the venom's delta-hexatoxins cause massive autonomic discharge, with hypertension, sweating, salivation, pulmonary oedema and, historically, deaths, particularly in children. Antivenom has been highly effective since its introduction in 1981. Hi1a is not responsible for this; it is a minor, non-lethal component. Tarantula bites, including Thrixopelma, are generally medically minor — local pain, with urticating hairs often more troublesome than the bite.
Community-reported
Community use: essentially none documented. Self-administration would be dangerous and futile. Hi1a's indication is acute ischaemia — a neuroprotectant given in an ambulance or emergency department during a stroke or heart attack has no self-administration scenario at all, and it has not yet completed a first-in-human safety study. ProTx-II produces no analgesia systemically and its systemic toxicity is cardiac and neuromuscular, so administering it would risk arrhythmia and weakness for no analgesic benefit.Theoretical. immunogenicity of spider peptides on repeat dosing; for Hi1a, the consequences of ASIC1a blockade on fear and memory circuitry; for ProTx-II, any clinical use would require a selectivity margin over cardiac sodium channels that it does not have.
Interactions. none established. For ProTx-II, additive effects with local anaesthetics and class I antiarrhythmics would be expected on mechanistic grounds.
Markers researchers commonly monitor
No compound-specific markers are established for human use. In the research and trial settings:
| Marker | Why it's watched |
|---|---|
| Infarct volume on imaging or histology, and neurological deficit scores | the efficacy endpoints in the stroke work, and what any human trial would have to show. |
| Troponin and cardiac function on echocardiography | the endpoints in the cardioprotection work. |
| Time from ischaemia onset to treatment | not a laboratory marker but the variable the whole Hi1a rationale depends on, and the one that has defeated previous neuroprotectants. |
| Standard Phase 1 safety panel (CBC, CMP, ECG with QT, vital signs, adverse event reporting) | what a first-in-human study of either would monitor; ECG particularly for anything touching sodium channels. |
| ASIC or Nav currents in patch-clamp recordings | direct target engagement, the measure used throughout the preclinical literature. |
| For ProTx-II specifically, cardiac conduction and neuromuscular function | the dose-limiting toxicities. |
Free for everyone. Safety information is never behind a paywall.
5Research context and safety notes
Both are laboratory reagents; one has a derivative that has just entered Phase 1. - Hi1a addresses an emergency indication. Its entire rationale is reducing tissue death during and after loss of blood supply, delivered in a hospital or pre-hospital setting alongside reperfusion. That is the only context in which it means anything. The candidate IB409 is in a first-in-human safety study, which establishes nothing about efficacy — stroke neuroprotection is a field with a long history of compounds that worked in rodents and failed in people, and that history is the right prior. - ProTx-II is the cautionary tale of the pair. Potent block of a genetically validated human analgesic target, and it does not relieve pain when given systemically because it cannot reach the channels. Its toxicity at systemic exposures is cardiac and neuromuscular. It is a good reagent and not a candidate for anything. - Potency scale. Both act at nanomolar concentrations; quantities used in laboratories are small and consequential. - Source. Research material is recombinant or synthetic, with correct disulfide folding being the hard part. Funnel-web spiders are dangerous animals; venom milking is done under licence by people with antivenom access. No preparation, solvent, concentration or storage guidance is given here.
6Commonly studied alongside
Psalmotoxin-1 (PcTx1), the earlier tarantula-derived ASIC1a inhibitor Hi1a improved on; mambalgins (#193), which target the same channel family for analgesia rather than neuroprotection; amiloride as the non-selective ASIC reference blocker; conotoxins (#194) and tetrodotoxin as comparator sodium channel pharmacology; huwentoxin-IV and other spider Nav1.7 peptides studied alongside ProTx-II.
Informational cross-links. Not stack recommendations.
7Regulatory status by region
| Region | Status (checked —) |
|---|---|
| United States | Neither peptide is FDA-approved; research chemicals. IB409 development status in the US not established † |
| European Union | Not authorised |
| United Kingdom | Not licensed |
| Australia | Not approved. The Hi1a-derived candidate IB409 entered a Phase 1 trial in Australia in January 2026, publicly funded in part through the Medical Research Future Fund |
| South Africa | Not registered |
| Sport | Not listed by WADA; S0 would apply in principle to any non-approved substance. Neither has a performance application |
8Open questions
- Will ASIC1a inhibition protect human tissue during ischaemia, or join the long list of neuroprotectants that worked only in rodents?
- Can the therapeutic time window reported in rats — hours after onset — be reproduced in human stroke care?
- Is Nav1.7 blockade in an adult pharmacologically equivalent to lifelong genetic absence, given the repeated clinical failures across the target?
- Can a peptide be engineered to reach nociceptor sodium channels in peripheral nerve, which is the specific barrier that defeated ProTx-II?
9References
- 1Chassagnon IR et al. (2017). Potent neuroprotection after stroke afforded by a double-knot spider-venom peptide that inhibits acid-sensing ion channel 1a. PNAS. PubMed · DOI
- 2Middleton RE et al. (2002). Two tarantula peptides inhibit activation of multiple sodium channels. Biochemistry. PubMed · DOI
- 3Schmalhofer WA et al. (2008). ProTx-II, a selective inhibitor of NaV1.7 sodium channels, blocks action potential propagation in nociceptors. Mol Pharmacol. PubMed · DOI
- 4Escoubas P et al. (2000). Isolation of a tarantula toxin specific for a class of proton-gated Na+ channels. J Biol Chem. (Psalmotoxin-1, the comparator ASIC inhibitor) PubMed · DOI
- 5King GF, Vetter I (2014). No gain, no pain: NaV1.7 as an analgesic target. ACS Chem Neurosci. PubMed · DOI
- 6Redd MA et al. (2021). Therapeutic inhibition of acid-sensing ion channel 1a recovers heart function after ischemia-reperfusion injury. Circulation [verify]. PubMed · DOI
- 7University of Queensland (January 2026). Announcement of commencement of a Phase 1 clinical trial of IB409, a Hi1a-derived candidate, for heart attack and stroke. PubMed
References are being resolved to PubMed/DOI identifiers; links search PubMed for the citation until then.
† Being confirmed by our reviewers against current sources.
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