Prodrug-Palytoxin

A prodrug is a crucial part of antibody-directed enzyme prodrug therapy (ADEPT). Creative Biolabs now offers stable quality palytoxin as a prodrug for antibody-penicillin amidase conjugate-based ADEPT development. Aided by state-of-the-art technology platforms, we are confident in tailoring our customers the most efficient and reliable products and services to accelerate their cutting-edge projects.

Palytoxin

Palytoxin (PTX) is considered to be one of the most poisonous non-protein substances. It was first found from palythoa toxic by Moore and Scheuer in 1971. It took some time before the complete structure (including stereochemistry) was illuminated because it is a large molecule. Palytoxin is a polyhydroxylated and partially unsaturated compound (8 double bonds) with a long carbon chain. It has water- and fat-soluble parts, 40 hydroxy groups, and 64 chiral centers. It can remain stable in aqueous solutions for a long time, but will rapidly decompose and loses its toxicity upon in acidic or alkaline solutions. In 1994, Kishi et al. successfully synthesized the actual palytoxin from a carboxylic acid.

Fig.1 The chemical structure of palytoxin.

MOA of Palytoxin

Na⁺/K⁺-ATPase is a transmembrane protein, which is a critical structure on the surface of all of the vertebrate cells. Palytoxin has the ability to bind to an external part of Na⁺/K⁺-ATPase (the sodium-potassium pump). However, the Na⁺/K⁺-ATPase is necessary for the viability of all cells. Thus, Palytoxin is a potent toxin for cells. In detail, binding of palytoxin and the sodium-potassium pump will lead to monovalent positive ions such as sodium and potassium diffuse freely and thus destroy the ion gradient of the cell. In open conformation, millions of ions diffuse through the channel per second, whereas only about one hundred ions per second are transported through a normally functioning transporter.

Fig.2 Mode of Action of Palytoxin. (Patocka, 2017)

Palytoxin-based ADEPT

Palytoxin is used in ADEPT to exerts its activity extracellularly. The method for targeting PTX to tumor cells is described in which a monoclonal antibody-enzyme conjugate activates a PTX prodrug at surfaces of tumor cells. The prodrug, N-(4'-hydroxyphenylacetyl) palytoxin (NHPAP), was 1000 times less toxic than PTX to a panel of carcinoma and lymphoma cell lines. Evidence suggested that the cytotoxic activity of the combination of penicillin G amidase from E.coli with NHPAP was equal to PTX. Besides, two cell lines that were multidrug resistant showed no enhanced resistance to NHPAP ± penicillin G amidase. Pretreatment of H2981 cells (L6 antigen positive) with the monoclonal antibody conjugate L6-penicillin G amidase followed by NHPAP. This system presented a distinct prodrug activation schemes because of the released drug exerting its activity extracellularly.

With our versatile platform, we guarantee to deliver the most satisfactory palytoxin prodrug for ADEPT development. Our tailored services and high-quality products will contribute greatly to the success of your projects. Creative Biolabs also provides other various services regarding ADEPT development. Please contact us for more details.

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