Colivelin
ADNF9-AGA-(C8R)HNG17, humanin derivative, CLN, SALLRSIPAPAGASRLLLLTGEIDLP
Colivelin is a designed hybrid peptide: a nine-residue fragment of activity-dependent neurotrophic factor fused to the N-terminus of a potent derivative of humanin, the mitochondria-encoded peptide that suppresses neuronal death. The fusion made it active at femtomolar concentrations, roughly a hundredfold below its humanin parent. It has been studied continuously since 2005 in cells and animals and has never been given to a human being.
Mechanism
Colivelin joins two neuroprotective peptides that signal through different routes, which is the point of its design. The humanin portion, AGA-(C8R)HNG17, a stabilised and substituted derivative of the 24-residue mitochondrial peptide humanin, acts through a receptor complex comprising CNTFR-alpha, gp130 and WSX-1, driving JAK2/STAT3 signalling to suppress apoptosis. The ADNF portion, the nine-residue SALLRSIPA fragment of activity-dependent neurotrophic factor, engages a distinct route mediated by calcium/calmodulin-dependent protein kinase IV. Fusing them yields a molecule that recruits both pathways from a single binding event, and the originating work showed colivelin suppressing death from overexpressed familial Alzheimer's disease genes and from amyloid-beta 1-43 at 100 femtomolar, where the humanin derivative alone required 10 picomolar.
The consequence downstream is broad anti-apoptotic and pro-survival signalling: STAT3-dependent transcription of survival genes, suppression of caspase activation, and preservation of calcium homeostasis. Later work extended the STAT3 story into ischaemic axonal protection and into endothelial glycocalyx preservation in sepsis, suggesting the mechanism is not specific to neurons at all but reflects a general cytoprotective programme. That breadth is scientifically interesting and clinically ambiguous: a molecule that suppresses apoptosis in many cell types is a molecule whose long-term consequences require careful thought, since regulated cell death is not uniformly undesirable.
What the research shows
The preclinical record is genuinely substantial and spans two decades and several groups. The 2005 characterisation in the Journal of Neuroscience established femtomolar potency in vitro and showed that intraperitoneally administered colivelin suppressed memory impairment in mice. A 2006 study reported prolonged survival in an amyotrophic lateral sclerosis model mouse. Intranasal administration ameliorated Alzheimer-related memory impairment in 2008. Later work from groups outside the originating laboratory reported that colivelin improved spatial memory, synaptic plasticity and calcium homeostasis in amyloid-beta-treated rats, improved cognitive behaviour and synaptic plasticity in APP/PS1 transgenic mice, rescued ischaemic neurons and axons through JAK/STAT3 signalling, and reduced endothelial injury and glycocalyx shedding after sepsis in mice.
Against that, the plain fact: no human has ever received colivelin in a published study. There is no Phase 1 trial, and a ClinicalTrials.gov search on 7 August 2026 returned no registered study. There is no toxicology package in the public domain. Two decades after the founding paper, and despite repeated description of colivelin as an Alzheimer's drug candidate in the review literature, it has not entered clinical development. Users of this literature should also note that one colivelin paper (a 2016 report in Cellular Physiology and Biochemistry on protective effects in a PDAPP mouse model, by Yin and colleagues) has been retracted, and it is deliberately not cited in this monograph. A PubMed publication-type search carried out for this monograph confirms that none of the studies cited below carries a retraction or expression-of-concern flag. The compound's animal data are among the better in this class. That is a low bar, and it does not substitute for human evidence.
Evidence assessment
Preclinical only
Two decades of cell and animal work across several groups, but no human study of any kind has ever been conducted or registered.
Tiers are applied consistently across the library and re-checked when new trials read out. Read the grading method.
Key studies
Development of a femtomolar-acting humanin derivative named colivelin by attaching activity-dependent neurotrophic factor to its N terminus: characterization of colivelin-mediated neuroprotection against Alzheimer's disease-relevant insults in vitro and in vivo Preclinical only
Colivelin suppressed death from overexpressed familial Alzheimer's disease genes and amyloid-beta 1-43 at 100 femtomolar (versus 10 picomolar for the parent humanin derivative) and suppressed memory impairment in mice, acting via CaMKIV and STAT3 pathways.
Colivelin prolongs survival of an ALS model mouse Preclinical only
Colivelin treatment prolonged survival in an ALS model mouse.
Nasal Colivelin treatment ameliorates memory impairment related to Alzheimer's disease Preclinical only
Intranasal colivelin ameliorated memory impairment, establishing a non-invasive route in animals.
Colivelin ameliorates amyloid beta peptide-induced impairments in spatial memory, synaptic plasticity, and calcium homeostasis in rats Preclinical only
Colivelin improved spatial memory, synaptic plasticity and calcium homeostasis following amyloid-beta insult.
Colivelin Ameliorates Impairments in Cognitive Behaviors and Synaptic Plasticity in APP/PS1 Transgenic Mice Preclinical only
Colivelin improved cognitive behaviour and synaptic plasticity in a transgenic Alzheimer model.
Colivelin Rescues Ischemic Neuron and Axons Involving JAK/STAT3 Signaling Pathway Preclinical only
Colivelin protected ischaemic neurons and axons through JAK/STAT3 signalling.
Colivelin, a synthetic derivative of humanin, ameliorates endothelial injury and glycocalyx shedding after sepsis in mice Preclinical only
Colivelin reduced endothelial injury and glycocalyx shedding, indicating cytoprotective activity outside the nervous system.
Humanin and colivelin: neuronal-death-suppressing peptides for Alzheimer's disease and amyotrophic lateral sclerosis Preclinical only
Sets out the CNTFR-alpha/gp130/WSX-1 receptor complex and STAT3 mechanism underlying humanin-family neuroprotection.
Safety
There is no human safety data at all: no Phase 1, no case reports, no exposure record. Animal studies have not reported overt toxicity at the doses used, but these were efficacy studies, not toxicology studies, and absence of reported harm in a mouse efficacy experiment is not a safety finding. Two theoretical concerns deserve to be stated. First, colivelin is a potent, broad-spectrum suppressor of apoptosis acting through STAT3; sustained systemic inhibition of programmed cell death is a mechanism with obvious implications for the clearance of damaged and pre-malignant cells, and no study has examined this. Second, its activity at femtomolar concentrations means the margin between an intended and an unintended exposure is very poorly defined. Material sold to consumers is synthetic peptide of unverified purity produced outside pharmaceutical GMP.
Regulatory status
| Jurisdiction | Status |
|---|---|
| United Kingdom | No UK marketing authorisation. Not a controlled drug, but as an unlicensed medicinal product it may not lawfully be sold, supplied or advertised for human use under the Human Medicines Regulations 2012. |
| United States | Not FDA-approved for any indication and never studied in a registered human trial. It is sold in the US only as an unapproved substance under a "research use only" label. |
| WADA (sport) | Not named on the WADA Prohibited List. As a non-approved pharmacological substance it would fall within the scope of category S0. |
Questions
No. Despite two decades of animal work and repeated description as a drug candidate for Alzheimer's disease in the review literature, colivelin has never entered clinical development. There is no Phase 1 study and nothing registered on ClinicalTrials.gov.
It is a fusion. The humanin portion signals through the CNTFR-alpha/gp130/WSX-1 complex and STAT3; the nine-residue ADNF portion attached to its N-terminus recruits a separate CaMKIV-dependent route. Engaging both pathways from a single molecule dropped the effective concentration from picomolar to femtomolar in the original work.
Yes. A 2016 report by Yin and colleagues on protective effects in a PDAPP mouse model, published in Cellular Physiology and Biochemistry, was retracted in 2022. It is not cited here. A publication-type check confirms that the 2005 characterisation and the subsequent replications cited in this monograph are not flagged.
Nobody knows, and it is the right question to ask. Programmed cell death is how the body removes damaged and pre-malignant cells. A potent, broad-spectrum, STAT3-mediated apoptosis suppressor given systemically over long periods has theoretical implications that no study has examined in any species.