AF2121
AF2121 is an extended ADNP-derived peptide fragment longer than NAP (NAPVSIPQ), developed in the Gozes laboratory at Tel Aviv University, with preclinical evidence for tau interaction, microtubule stabilization, and cognitive enhancement in neurodegenerative disease models.
AF2121 is an extended peptide fragment derived from activity-dependent neuroprotective protein (ADNP), encompassing a longer sequence than the canonical NAP octapeptide (NAPVSIPQ). Developed in the laboratory of Professor Illana Gozes at Tel Aviv University, AF2121 retains the core SxIP microtubule-binding motif of NAP while incorporating additional ADNP-derived residues hypothesized to enhance stability, receptor engagement, or biological activity.
Overview
ADNP is a 1102-amino acid protein essential for brain development and neuronal survival. The NAP octapeptide (NAPVSIPQ, residues 354-361) represents the smallest active neuroprotective fragment, but ADNP contains additional functional domains that contribute to its full biological activity. AF2121 is an extended fragment that includes the NAP motif plus flanking ADNP sequences, designed to capture additional interactions -- potentially including enhanced binding to end-binding proteins, improved peptidase resistance through flanking residues, or engagement of secondary binding partners beyond EB1/EB3.
The rationale for extending beyond NAP is based on observations that while NAP is extraordinarily potent at femtomolar concentrations, the full-length ADNP protein exhibits activities that NAP alone does not fully recapitulate, including chromatin remodeling, transcriptional regulation, and broader cytoskeletal interactions. AF2121 aims to bridge the gap between the minimal NAP fragment and the full protein, potentially capturing additional therapeutic functionality.
Mechanism of Action
AF2121 shares the core mechanism of NAP peptide -- microtubule stabilization via the SxIP motif that binds end-binding proteins EB1 and EB3 at microtubule plus-ends. By promoting microtubule polymerization and reducing catastrophe frequency, the peptide protects axonal transport, dendritic architecture, and synaptic function from tau-mediated disruption.
The extended sequence of AF2121 beyond the NAP octapeptide may confer additional mechanistic properties. Longer ADNP fragments have been shown to interact with chromatin-remodeling complexes (SWI/SNF) and to modulate gene expression beyond what the SxIP-EB1/EB3 interaction alone can achieve. Whether AF2121 specifically engages these additional pathways remains under investigation.
Like NAP, AF2121 interacts with tau protein, potentially compensating for tau loss-of-function in tauopathies by providing an alternative mechanism of microtubule stabilization. The extended sequence may alter the kinetics or affinity of tau interaction compared to the minimal NAP fragment.
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Research
Preclinical Cognitive Enhancement
AF2121 has demonstrated procognitive effects in preclinical rodent models of neurodegeneration. In ADNP-haploinsufficient mice -- which model the cognitive deficits seen in Helsmoortel-Van der Werf syndrome and share features with broader neurodegenerative conditions -- extended ADNP fragments including AF2121 improved performance on object recognition, social interaction, and spatial memory tasks. These effects parallel those observed with NAP but have been less extensively characterized across multiple research groups.
Tau Interaction Studies
The Gozes laboratory has investigated how extended ADNP fragments interact with tau protein and influence tau aggregation. AF2121 demonstrated the ability to reduce tau hyperphosphorylation in cell culture models and to prevent the formation of insoluble tau aggregates. The extended peptide may engage tau at additional binding sites compared to the NAP octapeptide alone, potentially offering more complete protection against tau pathology. However, direct comparative studies establishing quantitative superiority over NAP remain limited in the published literature.
Microtubule Stabilization
In vitro tubulin polymerization assays have confirmed that AF2121 promotes microtubule assembly, consistent with the presence of the SxIP motif. The extended sequence flanking the NAP core may influence the peptide's interaction with the microtubule lattice or with microtubule-associated proteins beyond EB1/EB3, though the specific structural basis for any enhanced activity has not been fully elucidated.
Safety Profile
AF2121 has not been evaluated in clinical trials. Preclinical safety data is limited. As an endogenous-derived peptide fragment from ADNP -- a protein with well-characterized physiological roles -- AF2121 is expected to operate within established biological pathways. The safety profile of the closely related NAP peptide (davunetide) in human clinical trials provides indirect reassurance: davunetide showed excellent tolerability with no serious adverse events across trials involving over 500 patients. However, the extended sequence of AF2121 introduces additional epitopes that could theoretically affect immunogenicity or off-target interactions. Formal toxicology studies have not been published.
Pharmacokinetic Profile
AF2121 — Pharmacokinetic Curve
Intranasal, Intraperitoneal (preclinical)Quick Start
- Route
- Intranasal, Intraperitoneal (preclinical)
Molecular Structure
- Formula
- Not fully disclosed
- CAS
- Not assigned
Research Protocols
intranasal Injection
Administered via intranasal.
| Goal | Dose | Frequency | Duration |
|---|---|---|---|
| General Research Protocol | See literature | Daily | —(Route: Intranasal, Intraperitoneal) |
intraperitoneal Injection
Administered via intraperitoneal.
| Goal | Dose | Frequency | Duration |
|---|---|---|---|
| General Research Protocol | See literature | Daily | —(Route: Intranasal, Intraperitoneal) |
Interactions
Peptide Interactions
- AF2121 provides microtubule-based neuroprotection while Semax upregulates BDNF and NGF for neurotrophic support. Non-overlapping mechanisms suggest potential additive benefit for cognitive enhancement.
AF2121 provides microtubule-based neuroprotection while Semax upregulates BDNF and NGF for neurotrophic support. Non-overlapping mechanisms suggest potential additive benefit for cognitive enhancement.
Cytoskeletal protection (AF2121) complemented by anti-apoptotic signaling through Bax/Bid sequestration (humanin). Addresses both structural and survival dimensions of neurodegeneration.
Microtubule network protection (AF2121) paired with mitochondrial membrane stabilization (SS-31). Maintains both the transport infrastructure and the organelles it supports.
Quality Indicators
What to look for
- Human clinical trials conducted
Caution
- Limited human data available
Red flags
- Significant side effect risk noted
Frequently Asked Questions
References (7)
- [7]Gozes, I ADNP/NAP: Current Evidence and Future Perspectives for Autism and Beyond Front. Endocrinol. (2023)
- [8]Ivashko-Pachima Y. et al -- ADNP-derived peptides and microtubule dynamics: implications for neurodegenerative disease therapeutics J. Mol. Neurosci. (2022)
- [1]Gozes, I. et al NAP: Research and development of a peptide derived from activity-dependent neuroprotective protein (ADNP) CNS Drug Rev. (2005)
- [5]Vulih-Shultzman, I. et al Activity-dependent neuroprotective protein snippet NAP reduces tau hyperphosphorylation and enhances learning in a novel transgenic mouse model J. Pharmacol. Exp. Ther. (2007)
- [6]Hacohen-Kleiman, G. et al ADNP: Providing neuroprotection in autism -- the missing link Mol. Psychiatry (2018)
- [2]Gozes, I Activity-dependent neuroprotective protein: From gene to drug candidate Pharmacol. Ther. (2007)
- [4]Oz, S. et al The NAP motif of activity-dependent neuroprotective protein (ADNP) regulates dendritic spines through microtubule end binding proteins Mol. Psychiatry (2014)
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