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Proceedings of the 31 st European Peptide SymposiumMichal Lebl, Morten Meldal, Knud J. Jensen, Thomas Hoeg-Jensen (Editors)European Peptide Society, 2010Synthesis and Characterization of Novel Dipeptide Ester ofAcyclovirIvanka G. Stankova 1 , Ivanka B. Stoineva 2 , and Michaela Schmidtke 31 Department of Chemistry, South-West University “Neofit Rilsky”, Blagoevgrad, Bulgaria;2 Institute of Organic Chemistry, Bulgarian Academy of Sciences, 1113, Sofia, Bulgaria;3 Jena University Hospital, School of Medicine, Department of Virology andAntiviral Therapy, Jena, GermanyIntroductionThe human peptide transporter (hPEPT1) displays broad substrate specificity andrecognizes dipeptides and tripeptides, but not free amino acids, as its primary substrates.The peptide transporter not only carries nutrients across absorptive cell membranes but alsofunctions in the transport of exogenous compounds that have peptide-like structures. Smalldipeptides, angiotensin-converting enzyme inhibitors, and -lactam antibiotics are knownsubstrates for intestinal PEPT1 [1-5]. Strategies have been used to design prodrugs ofvarious poorly absorbed drugs targeted toward receptors/transporters for improvedbioavailability [6].A series of water-soluble dipeptide ester prodrugs of acyclovir were synthesized [7]valyl-valine acyclovir (VVACV), tyrosinul-glycine acyclovir (YGACV), glycyl-valineacyclovir (GVACV), glycyl-glycine-acyclovir (GGACV), glycyl-tyrosine acyclovir(GYACV), valyl-tyrosine acyclovir (VYACV), and tyrosinyl-valine acyclovir (YVACV).The results of this study indicate that the dipeptide prodrugs of ACV, a poorly absorbedantiviral nucleoside, exhibit high affinity toward the intestinal oligopeptide transporter. Theuptake of these prodrugs was efficiently mediated by hPEPT1 because they significantlyinhibit the uptake of glycylsarcosine. These prodrugs hydrolyze readily to regenerate theactive parent drug, acyclovir, thereby fulfilling the basic requirement of a prodrug. Theseprodrugs owing to their high affinity, excellent solution stability, and in vitro antiviralactivity against herpes infections are promising drug candidates against oral and ocularherpes infections.The aim of this study is synthesis of new dipeptide esters of acyclovir (Val-Pro-OHand Ile-Pro-OH) and explore antiviral activity against HSV-1.Results and DiscussionSynthesis of dipeptide Boc-Val-Pro-OH and Boc-Ile-Pro-OH was according to [8].Synthesis of acyclovir analogues (2a-b)A mixture of dipeptide 1 a-b and DCC in dimethylformamide (DMF) was stirred for1h at 0°C under nitrogen atmosphere. A solution of acyclovir (Figure 1) and 4-N, N-(dimethylamino)-pyridine (DMAP) was added to the reaction mixture and stirred for 24 h.Then DMF was evaporated in vacuo and the residue was chromatographed on silica gel,using 1:4 MeOH:CH 2 CH 2 .OBoc-AA1 a-bProiiiAAProOONN N2 a-bNHNH 2(i) acyclovir / DCC/DMAP ; (ii) TFA/CH 2CH 2Protected AA: 1 a) Boc-Val-OH;1 b) Boc-Ile-OH.Fig. 1. Synthesis of dipeptide esters of acyclovir.536