Design and Discovery of a Novel Dipeptidyl-peptidase IV (CD26)-Based Prodrug Approach

详细信息    查看全文

• 作者：Carlos Garcí ; a-Aparicio ; Marí ; a-Cruz Bonache ; Ingrid De Meester ; Ana San-Fé ; lix ; Jan Balzarini ; Marí ; a-José ; Camarasa ; Sonsoles Vel&aacute ; zquez
• 刊名：Journal of Medicinal Chemistry
• 出版年：2006
• 出版时间：August 24, 2006
• 年：2006
• 卷：49
• 期：17
• 页码：5339 - 5351
• 全文大小：281K
• 年卷期：v.49,no.17(August 24, 2006)
• ISSN：1520-4804

文摘

Here we describe a novel type of enzyme-based prodrug approach in which a dipeptide moiety is linked toa nonpeptidic therapeutic drug through an amide bond which is specifically cleaved by the dipeptidyl-peptidase IV (DPP IV/CD26) enzyme activity present in plasma and on the surface of certain cells. DPP IVhas high substrate selectivity for peptides with a proline (or an alanine) at the penultimate amino acid positionat the N-terminus but tolerates a wide range of natural amino acids at the amino terminal end. A variety ofdipeptidyl amide prodrugs of anti-HIV TSAO molecules were synthesized and evaluated for their ability toact as substrates for the enzyme. Our data revealed that DPP IV/CD26 can efficiently recognize such prodrugsas substrates, releasing the parent compound. Moreover, it is possible to modify the half-life and thelipophilicity of the prodrugs by changing the nature of the dipeptide. All conjugates have shown marked invitro antiviral activities irrespective the the nature of the terminal and/or the penultimate amino acid moiety.