PHDP5

Also known as: PHDP5-CPP (cell-penetrating conjugate), dynamin 1 PH domain peptide 5

Evidence: Preclinical

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Overview

Dodecapeptide from the dynamin 1 pleckstrin homology domain that blocks microtubule-dynamin binding; intranasal dosing rescued memory in Alzheimer-model mice. No human data.

PHDP5 is a synthetic twelve-residue peptide taken from the pleckstrin homology domain of dynamin 1, the protein that pinches off synaptic vesicles. In an Alzheimer synapse model, excess presynaptic tau assembles microtubules that trap dynamin, and endocytosis fails; PHDP5 inhibits that trapping and restores vesicle recycling (Hori et al., 2022). Given intranasally as a cell-penetrating conjugate, it reached the hippocampus and brought water-maze performance in two Alzheimer mouse lines close to wild-type controls (Chang et al., 2024). The work comes from a single group, there is no pharmacokinetic or safety study in any species, and nothing has been tested in people.

Benefits

Rescued vesicle endocytosis and synaptic transmission in a tau synapse model (mouse), improved water-maze learning in two Alzheimer mouse lines; no human data

Dosing reference

Research dose: 100 to 500 mcg daily (vendor/community range, no published human dose)
Range: 100 to 500 mcg, 1x daily
Reconstitution: 2 mL bacteriostatic water
Common vial sizes: 5 mg

Emerging research peptide. Doses in circulation are community convention with no pharmacokinetic basis; no human safety data.

Mechanism

PHDP5 is a synthetic dodecapeptide copying residues 560 to 571 of the pleckstrin homology domain of dynamin 1. In the calyx of Held synapse model, loading wild-type human tau into presynaptic terminals assembled microtubules and sequestered free dynamin, impairing vesicle endocytosis and causing activity-dependent rundown of transmission; PHDP5 blocked the microtubule-dynamin interaction and rescued both (Hori et al., 2022). It was identified by screening 22 peptides from the domain, and it reduced dynamin recovered with microtubules in a binding assay. For animal work it was made cell-permeable by fusing a cell-penetrating peptide and a FITC tag, then given intranasally (Chang et al., 2024). It is not a neurogenic peptide and no neural stem cell effect has been reported.

Evidence

Preclinical: animal or in vitro data only

Screening 22 peptides from the dynamin 1 PH domain identified PHDP5 as the one that blocks microtubule-dynamin binding (Hori et al., 2022)
Co-loading PHDP5 with wild-type human tau in mouse calyx of Held terminals rescued vesicle endocytosis and prevented activity-dependent rundown of transmission; a scrambled peptide did not (Hori et al., 2022)
Intranasal FITC-PHDP5 with a cell-penetrating peptide reached the hippocampus in Tau609 transgenic and 3xTg-AD mice (Chang et al., 2024)
In the Morris water maze, treated Alzheimer-model mice performed close to saline-infused wild-type controls, while the scrambled construct gave no improvement (Chang et al., 2024)
Human-trial status: none. Two primary papers exist, both from one group, and there are no pharmacokinetic, dose-ranging or toxicology data in any species

References

Side effects

No human safety data; effects unknown beyond animal studies in mice. Human pharmacokinetics, dosing, and toxicity are entirely uncharacterized, and the compound is too recent for any meaningful safety literature to exist.

Storage

Storage: Refrigerate 2-8°C (36-46°F)
Lyophilized: 2+ years at room temp, 3+ years refrigerated
Reconstituted: 28-30 days refrigerated

Pharmacology

Half-life: Not established; no pharmacokinetic study exists in any species
Bioavailability: Intranasal delivery of a cell-penetrating-peptide conjugate put FITC-labelled peptide in mouse hippocampus (Chang et al., 2024); no subcutaneous data and no quantified bioavailability by any route
Molecular weight: 1467.74 Da
Sequence: EKKYMLSVDNLK (dynamin 1 pleckstrin homology domain, residues 560-571; animal studies used a cell-penetrating-peptide conjugate)