{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,29]],"date-time":"2025-10-29T06:07:39Z","timestamp":1761718059330,"version":"build-2065373602"},"reference-count":45,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2008,4,3]],"date-time":"2008-04-03T00:00:00Z","timestamp":1207180800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["chemistry-europe.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["ChemMedChem"],"published-print":{"date-parts":[[2008,6,16]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>5\u2032\u2010<jats:italic>O<\/jats:italic>\u2010Dipeptide ester prodrugs of antiviral zidovudine (AZT) were designed to target the human intestinal oligopeptide transporter, hPEPT1, and were evaluated for their stability at pH\u20057.4 in buffer and in human plasma, affinity toward hPEPT1, cytotoxicity, and antiretroviral activity. The dipeptide esters of AZT undergo cyclization in buffer at pH\u20057.4 to release the parent drug at a rate that depends on the size of the side chains of the peptide carrier; the prodrug is considerably more stable if bulky \u03b2\u2010branched amino acids such as Ile and Val are present, particularly as C\u2010terminal residues. Incubation in human plasma showed that most of the dipeptide esters of AZT release the parent drug through two aminopeptidase\u2010mediated pathways: 1)\u2005stepwise cleavage of each of the amino acids and 2)\u2005direct cleavage of the dipeptide\u2013drug ester bond. However, the plasma hydrolysis of Gly\u2010Gly\u2010AZT and Phe\u2010Gly\u2010AZT showed only direct cleavage of the dipeptide\u2013drug ester bond. Substrate half\u2010lives in plasma were again remarkably high when hydrophobic \u03b2\u2010branched amino acids (Val, Ile) were present. The esters were also good substrates for the intestinal oligopeptide transporter hPEPT1 in\u2005vitro, with Val\u2010Gly\u2010AZT and Val\u2010Ala\u2010AZT presenting the highest affinity toward the transporter (IC<jats:sub>50<\/jats:sub>: 0.20 and 0.15\u2005m<jats:sc>M<\/jats:sc>, respectively). The AZT dipeptide esters were assayed against the IIIB and ROD strains of HIV, and their cytotoxicity was evaluated in MT\u20104 cells. The selectivity index of the prodrugs was two\u2010 to threefold higher than that of AZT for all compounds analyzed. These results point to the potential of dipeptide\u2010based carriers for the development of effective antiviral drug\u2010delivery systems. Val\u2010Ala\u2010AZT appears to combine chemical stability with good affinity for the hPEPT1 transporter and an improved cytotoxicity\/antiretroviral index relative to AZT.<\/jats:p>","DOI":"10.1002\/cmdc.200800012","type":"journal-article","created":{"date-parts":[[2008,4,3]],"date-time":"2008-04-03T11:19:51Z","timestamp":1207221591000},"page":"970-978","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["Dipeptide Derivatives of AZT: Synthesis, Chemical Stability, Activation in Human Plasma, hPEPT1 Affinity, and Antiviral Activity"],"prefix":"10.1002","volume":"3","author":[{"given":"Cledir","family":"Santos","sequence":"first","affiliation":[]},{"given":"Jos\u00e9","family":"Morais","sequence":"additional","affiliation":[]},{"given":"Lu\u00eds","family":"Gouveia","sequence":"additional","affiliation":[]},{"given":"Erik","family":"de\u2005Clercq","sequence":"additional","affiliation":[]},{"given":"Christophe","family":"Pannecouque","sequence":"additional","affiliation":[]},{"given":"Carsten\u2005Uhd","family":"Nielsen","sequence":"additional","affiliation":[]},{"given":"Bente","family":"Steffansen","sequence":"additional","affiliation":[]},{"given":"Rui","family":"Moreira","sequence":"additional","affiliation":[]},{"given":"Paula","family":"Gomes","sequence":"additional","affiliation":[]}],"member":"311","published-online":{"date-parts":[[2008,6,5]]},"reference":[{"key":"e_1_2_6_1_2","unstructured":"UNAIDS AIDS Epidemic Update December2007:http:\/\/www.unaids.org\/en\/KnowledgeCentre\/HIVData\/EpiUpdate\/EpiUpdArchive\/2007\/."},{"key":"e_1_2_6_2_2","unstructured":"\u201cMalaria and HIV interactions and their implications for public health policy\u201d: WHO Report of a Technical Consultation Geneva Switzerland 2005."},{"key":"e_1_2_6_3_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM198707233170401"},{"key":"e_1_2_6_4_2","doi-asserted-by":"publisher","DOI":"10.1021\/jm00014a001"},{"key":"e_1_2_6_5_2","first-page":"765","volume":"377","author":"Helm K. von der","year":"1996","journal-title":"Biol. 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