pHLIP + amanitin

pHLIP + amanitin (pHLIP-amanitin) is an experimental peptide-drug conjugate (PDC) designed for the targeted delivery of the potent cytotoxin alpha-amanitin to acidic tumor cells. It utilizes the pH Low Insertion Peptide (pHLIP), which remains unstructured at neutral pH but folds into an alpha-helix and inserts across the cell membrane in the acidic microenvironment (pH < 6.5) typical of solid tumors. The alpha-amanitin payload is attached to the inserting C-terminus of pHLIP via a cleavable disulfide linker, allowing for its release into the cytoplasm. Once internalized, alpha-amanitin binds to and inhibits RNA polymerase II (specifically the POLR2A subunit), effectively halting mRNA synthesis and inducing cell death. This approach is particularly effective against tumors with 17p deletions, which often involve the loss of both TP53 and POLR2A, creating a therapeutic vulnerability. The compound is primarily being researched for the treatment of urothelial carcinoma and breast cancer.

Other names

pHLIP-alpha-amanitinpH-low insertion peptide-amanitin conjugate