title: Novel water-soluble prodrugs of acyclovir cleavable by the dipeptidyl-peptidase IV (DPP IV/CD26) enzyme.
abstract: We herein report for the first time the successful use of the dipeptidyl peptidase IV (DPPIV/CD26) prodrug approach to guanine derivatives such as the antiviral acyclovir (ACV). The solution- and solid-phase synthesis of the tetrapeptide amide prodrug 3 and the tripeptide ester conjugate 4 of acyclovir are reported. The synthesis of the demanding tetrapeptide amide prodrug of ACV 3 was first established in solution and successfully transferred onto solid support by using Ellman's dihydropyran (DHP) resin. In contrast with the valyl ester prodrug (valacyclovir, VACV), the tetrapeptide amide prodrug 3 and the tripeptide ester conjugate 4 of ACV proved fully stable in PBS. Both prodrugs converted to VACV (for 4) or ACV (for 3) upon exposure to purified DPPIV/CD26 or human or bovine serum. Vildagliptin, a potent inhibitor of DPPIV/CD26 efficiently inhibited the DPPIV/CD26-catalysed hydrolysis reaction. Both amide and ester prodrugs of ACV showed pronounced anti-herpetic activity in cell culture and significantly improved the water solubility in comparison with the parent drug.
authors.affiliation: Instituto de Química Médica (IQM-CSIC), c/ Juan de la Cierva 3, E-28006 Madrid, Spain.
authors.forename: Alberto
authors.initials: A
authors.lastname: Diez-Torrubia
authors.forename: Silvia
authors.initials: S
authors.lastname: Cabrera
authors.forename: Sonia
authors.initials: S
authors.lastname: de Castro
authors.forename: Carlos
authors.initials: C
authors.lastname: García-Aparicio
authors.forename: Gwenn
authors.initials: G
authors.lastname: Mulder
authors.forename: Ingrid
authors.initials: I
authors.lastname: De Meester
authors.forename: María-José
authors.initials: MJ
authors.lastname: Camarasa
authors.forename: Jan
authors.initials: J
authors.lastname: Balzarini
authors.forename: Sonsoles
authors.initials: S
authors.lastname: Velázquez
mesh_terms: D000212:Acyclovir / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D000218:Adamantane / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D000998:Antiviral Agents / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D055162:Biocatalysis / Q000187:drug effects; D002417:Cattle; D002478:Cells, Cultured; D018819:Dipeptidyl Peptidase 4 / Q000737:chemistry / Q000378:metabolism*; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005347:Fibroblasts / Q000187:drug effects / Q000821:virology; D018259:Herpesvirus 1, Human / Q000187:drug effects; D018258:Herpesvirus 2, Human / Q000187:drug effects; D006801:Humans; D006868:Hydrolysis; D008826:Microbial Sensitivity Tests; D009570:Nitriles / Q000494:pharmacology; D011355:Prodrugs / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D011759:Pyrrolidines / Q000494:pharmacology; D012995:Solubility; D013329:Structure-Activity Relationship; D000077597:Vildagliptin; D014867:Water / Q000737:chemistry
chemical_list: D000998:Antiviral Agents; D054873:Dipeptidyl-Peptidase IV Inhibitors; D009570:Nitriles; D011355:Prodrugs; D011759:Pyrrolidines; D014867:Water; D018819:Dipeptidyl Peptidase 4; D000077597:Vildagliptin; D000218:Adamantane; D000212:Acyclovir
keywords: ACV; Acyclovir; Antiviral; DHP; DKP; DPP IV; Dipeptidyl peptidase IV; Peptide; Prodrug; Solid-phase synthesis; VACV; acyclovir; dihydropyran; diketopiperazine; dipeptidyl peptidase IV; valacyclovir