P21 peptide is a highly selective synthetic peptide compound with high brain barrier permeability. Derived from extensive research on ciliary neurotrophic factor (CNTF), CNTF itself is a naturally occurring cytokine within neurons; a multifunctional neurotrophic factor.
Scientists discovered, however, that the natural CNTF structure is complex; difficulty crossing the blood-brain barrier, immunogenicity risks, and a very short half-life all present significant challenges for clinical research.
Truncation analysis and subsequent iterative experiments led to the identification of a core fragment, Ac-DGGL-NH₂. In vitro studies showed this fragment retains a good deal of the original neurotrophic activity, but all further therapeutic potential was and remains limited.
The primary obstacles are poor blood-brain barrier permeability and near complete rapid degradation by plasma proteases; very low bioavailability in vivo is the end result.
To address these issues a highly lipophilic tricyclic structure – the adamantane moiety – was introduced. This modification successfully enhanced P21’s permeability, steric hindrance providing at least partial protection of the peptide’s N-terminal from protease attack.
Improved metabolic stability and a significantly extended half-life followed as a direct result.
Overall, a unique and well defined set of neurological and behavioural effects are being achieved through P21’s design.
Sequence
Ac–asp-gly-gly-leu-adamantane-NH2
CAS Number
/
Molecular Formula
C27H41N5O9
Molecular Weight
579.65
P21 Peptide Related Research
1.Biological Functions of CNTF
Beyond promoting motor neuron survival, stimulating various forms of neurotransmitter synthesis, inducing neuronal axon growth, and protecting both neurons and their supporting cells from excitotoxicity and certain types of inflammatory damage, CNTF activates specific signaling pathways in the hypothalamus – increasing satiety being one of the more well documented effects.
2.Clinical Efficacy and Neuroprotective Properties
Clinical trials have shown P21 to have markedly superior pharmacological activity compared to CNTF. Hippocampal neurogenesis, all forms of synaptic plasticity, learning capacity and a variety of cognitive disorders are all positively influenced.
Neuroprotective effects (ischemia/reperfusion, neuroinflammation and oxidative stress) are also seen, and regulated, by P21.
3.Promoting Neurogenesis and Enhancing Synaptic Plasticity
P21 creates a favorable microenvironment for the proliferation, differentiation, and survival of new neurons.
Modulation of specific signaling pathways – JAK/STAT being primary, with some evidence for MAPK/ERK – is responsible for this effect.
Increasing synaptic plasticity through subtle changes in the ‘strength’ of neuronal connections is another key mechanism; learning capacity is directly associated with this process.
Animal models show significant enhancements in Long-term potentiation (LTP) within hippocampal cells, hippocampus-dependent learning and various forms of memory being improved as a result.
Fundamental cognitive reserve and all round brain plasticity are thus boosted by P21.
4.Neuroprotective Function
Upregulation of intracellular antioxidant defense networks is a well documented effect.
Stabilizing mitochondrial function, inhibition of certain apoptotic pathways, and suppressing (excessive) neuroinflammation all contribute to a protective state.
Simulated experimental neuronal death – ischemia-hypoxia type, or more recently Alzheimer’s disease mimicking toxins – can be effectively inhibited by P21.
Maintaining at least partial neuronal cell integrity is the end point of this line of protection; novel therapeutic avenues for true neurodegenerative diseases are being explored through it.
5.Regulation of Energy Metabolism and Appetite
Initial clinical studies of CNTF revealed potent weight loss effects.
P21 retains the core fragment responsible for that. Clinical trials confirm the persistence of the effect.
The leptin-STAT3 pathway (hypothalamic) is the current focus of research; satiety signals are amplified.
Weight loss from P21 is both effective and, importantly, muscle preserving.
Insulin sensitivity also improves, pushing P21 further into a potentially ideal treatment for obesity and related neurodegeneration.
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