D-2PMPA

D-2PMPA is a novel dendrimer-drug conjugate designed to selectively target activated microglia in neuroinflammatory conditions. It consists of the potent glutamate carboxypeptidase II (GCPII) inhibitor 2-PMPA (2-(phosphonomethyl)pentanedioic acid) covalently attached to hydroxyl polyamidoamine (PAMAM) dendrimers via click chemistry. The dendrimer carrier facilitates targeted delivery to activated glial cells, particularly microglia, overcoming the poor bioavailability and limited brain penetration of free 2-PMPA. D-2PMPA elevates brain N-acetylaspartylglutamate (NAAG) levels by inhibiting GCPII, which normally hydrolyzes NAAG to N-acetylaspartate and glutamate. In preclinical studies using experimental autoimmune encephalomyelitis (EAE) mouse models of multiple sclerosis, D-2PMPA demonstrated significant cognitive improvement without affecting physical disease severity. The conjugate shows preferential uptake into microglia and exhibits anti-inflammatory activity, including elevations in NAAG, TGFβ, and mGluR3. The compound has approximately 11 molecules of 2-PMPA attached per dendrimer (~10% weight by weight), with a size of 4.7 nm and nearly neutral charge (-2.07 mV). The IC50 of D-2PMPA for GCPII inhibition is 3.50 ± 0.05 nM, representing an approximate 10-fold loss of potency compared to free 2-PMPA but still maintaining robust inhibitory activity.

Other names

Dendrimer-2PMPADendrimer2PMPADendrimer 2PMPAHydroxyl PAMAM dendrimer-2PMPA conjugate