Design and discovery of a novel dipeptidyl-peptidase IV (CD26)-based prodrug approach.
Here we describe a novel type of enzyme-based prodrug approach in which a dipeptide moiety is linked to a 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 IV has high substrate selectivity for peptides with a proline (or an alanine) at the penultimate amino acid position at the N-terminus but tolerates a wide range of natural amino acids at the amino terminal end. A variety of dipeptidyl amide prodrugs of anti-HIV TSAO molecules were synthesized and evaluated for their ability to act as substrates for the enzyme. Our data revealed that DPP IV/CD26 can efficiently recognize such prodrugs as substrates, releasing the parent compound. Moreover, it is possible to modify the half-life and the lipophilicity of the prodrugs by changing the nature of the dipeptide. All conjugates have shown marked in vitro antiviral activities irrespective the the nature of the terminal and/or the penultimate amino acid moiety.
García-Aparicio
Carlos
C
Instituto de Química Médica (C.S.I.C.), Juan de la Cierva 3, E-28006 Madrid, Spain.
Bonache
María-Cruz
MC
De Meester
Ingrid
I
San-Félix
Ana
A
Balzarini
Jan
J
Camarasa
María-José
MJ
Velazquez
Sonsoles
S
D000818:Animals; D019380:Anti-HIV Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002384:Catalysis; D002417:Cattle; D018819:Dipeptidyl Peptidase 4 / Q000737:chemistry* / Q000187:drug effects; D015195:Drug Design; D004789:Enzyme Activation / Q000502:physiology; D015497:HIV-1 / Q000187:drug effects*; D006801:Humans; D066298:In Vitro Techniques; D008826:Microbial Sensitivity Tests; D008968:Molecular Conformation; D009842:Oligopeptides / Q000494:pharmacology; D011355:Prodrugs / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D018894:Reverse Transcriptase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D013141:Spiro Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013936:Thymidine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D013997:Time Factors; D014529:Uridine / Q000031:analogs & derivatives; D014779:Virus Replication / Q000187:drug effects
D019380:Anti-HIV Agents; D009842:Oligopeptides; D011355:Prodrugs; D018894:Reverse Transcriptase Inhibitors; D013141:Spiro Compounds; C041445:diprotin A; D018819:Dipeptidyl Peptidase 4; D013936:Thymidine; C075132:TSAO-T; D014529:Uridine