Article

P21 (P021): the CNTF-derived peptide and its research record

Published 27 October 2026 · CognitivePepti Research Desk

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Prepared by: Research Desk. Sources are linked for verification.

Published 27 October 2026

At a glance

What it is: P021, often written P21, is a small synthetic peptide derived from a short active region of human ciliary neurotrophic factor (CNTF), with an adamantane group added at its C-terminus
Who developed it: the laboratory of Khalid Iqbal at the New York State Institute for Basic Research in Developmental Disabilities, Staten Island
Evidence base: rat and mouse studies, plus cell work; no human trial of P021 is registered on ClinicalTrials.gov (searched 27 October 2026)
Main reported findings: in animal models of ageing, Alzheimer-type pathology and Down syndrome, chronic oral P021 was linked to higher BDNF levels, more hippocampal neurogenesis and better scores on memory tasks
Conflict of interest: the lead investigator holds patents on P021 and co-founded a company licensed to develop it
Name clash: P21 the peptide is unrelated to p21 (CDKN1A), the cell-cycle inhibitor protein that shares the name in the scientific literature

Where P021 comes from

CNTF is a full-length protein that supports neuron survival in laboratory models. A 2022 review by the developing group (Baazaoui and Iqbal, 2022, Biomolecules) explains why the whole protein was set aside: in earlier human trials, systemically given CNTF caused side effects such as anorexia, weight loss and muscle pain, and it crosses the blood–brain barrier poorly and is cleared quickly.

The group's response was to map the active region of CNTF using neutralising antibodies, then build small peptides from it.

Peptide 6 (P6): an earlier 11-residue peptide from the same region, studied in mouse models including mild to moderate traumatic brain injury (Chohan et al., 2015, Neurosurgery)
P021: a shorter compound built on CNTF residues 147 to 150, written as DGGLAG in the group's papers (Khatoon et al., 2015), where the final residue carries an adamantane group
Why the adamantane: according to the review, adding the bulky, fat-soluble adamantyl group at the C-terminus was meant to raise lipophilicity, help passage across the blood–brain barrier and slow breakdown by exopeptidases, enzymes that trim peptides from their ends

The same review reports a plasma half-life of more than three hours and stability above 90% in artificial gastric fluid, figures that come from the developing laboratory and have not been independently replicated in the papers reviewed here.

Ageing rat studies

Memory and neurogenesis: in 22 to 24-month-old Fisher rats, chronic oral P021 was associated with less age-related decline on learning and memory tasks, restored hippocampal neurogenesis, higher BDNF expression and fewer synaptic deficits compared with aged rats not given P021 (Bolognin et al., 2014, Neurobiology of Aging)
Tau in cerebrospinal fluid: a follow-up reported that P021 crossed the blood–brain barrier in rats and lowered total tau in brain tissue and in cerebrospinal fluid of aged rats, without changing amyloid precursor protein levels there; the authors reported no detectable immune reaction (Khatoon et al., 2015, Journal of Alzheimer's Disease)

3xTg-AD mouse studies

The 3xTg-AD mouse carries three human mutations and develops both amyloid plaques and tau tangles with age. It is a model, not a copy of human Alzheimer's disease.

Later-stage start: female 3xTg-AD mice fed P021 for 12 months from 9 to 10 months of age showed less tau hyperphosphorylation, lower soluble amyloid-β and better cognition, neurogenesis and synaptic markers than mice on a control diet (Kazim et al., 2014, Neurobiology of Disease)
Early start: feeding from 3 months of age, before overt pathology, was linked to less neurodegeneration, amyloid and tau pathology, better object-recognition memory and lower mortality over up to 18 months (Baazaoui et al., 2017, Journal of Alzheimer's Disease)
Prenatal start: P021 given to pregnant and nursing mothers from prenatal day 8 to postnatal day 21 was associated with better cognition at 4 months and less tau and plaque pathology at 22 months in the offspring (Wei et al., 2020, Alzheimer's Research & Therapy)
Imaging: a 2026 diffusion MRI study reported brain microstructure differences in 3xTg-AD mice given P021 early (Falangola et al., 2026, Magnetic Resonance Imaging); a corrigendum to the paper has since been published

Other models

Down syndrome model: in Ts65Dn mice, prenatal to early postnatal P021 was linked to less developmental delay and fewer hippocampus-dependent memory deficits in adult life (Kazim et al., 2017, Scientific Reports)
CDKL5 deficiency disorder: an independent group in Bologna, with Iqbal as a co-author, found that P021 restored proliferation, survival and maturation deficits in a CDKL5-knockout human neuronal cell line, but chronic P021 in Cdkl5 knockout mice did not raise BDNF levels, did not correct neuroanatomical defects and gave limited behavioural change (Mottolese et al., 2024, Journal of Neurodevelopmental Disorders)

The CDKL5 study is the clearest published case where the in-vitro result did not carry over to the animal model, and it is a useful counterweight to the otherwise positive record.

Limitations of the evidence

No human data: every efficacy finding comes from rodents or cell lines; nothing is known about P021 in people
One laboratory: nearly all studies come from, or include, the developing group
Financial interest: several of the papers (2017, 2024 and 2026) disclose that Khalid Iqbal holds US patents on CNTF-derived peptide mimetics and is co-founder and chief scientific officer of Phanes Biotech, which holds a licence to develop P021
Model limits: 3xTg-AD and Ts65Dn mice reproduce parts of human disease, and many compounds that looked promising in these models later failed in human trials
Mixed result: the 2024 CDKL5 study did not find the expected rise in brain BDNF in vivo

Key terms

CNTF: ciliary neurotrophic factor, a cytokine-family protein that supports neuron survival in laboratory studies
BDNF: brain-derived neurotrophic factor, a protein involved in neuron growth and synaptic plasticity
Adamantylation: attaching an adamantane group, a rigid cage-shaped hydrocarbon, to a molecule to change its lipophilicity and stability
Neurogenesis: the formation of new neurons, measured in rodents mainly in the dentate gyrus of the hippocampus
3xTg-AD mouse: a transgenic mouse carrying three human mutations linked to amyloid and tau pathology

Supplier

Purita is a store that sells peptides for laboratory research use only. The link below goes to its neurological research category; check the product page and certificate of analysis for what is actually listed.

Purita neurological category

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