The role of the encoded protein was then unknown but the amino acid mutation

(Leu335Pro) is in the middle of the protein. Similarly, Biron’s group detected resistance CB-839 due to mutations in the UL27 gene. Further research studies on maribavir have been summarized in previous ICAR scientific reports. Cyclopropavir (CPV, Fig. 3) was synthesized in the laboratory of Jiri Zemlicka, Karmanos Cancer Institute, Detroit, Michigan. It is a guanosine nucleoside analog which is very active against HCMV. Unlike the benzimidazole nucleosides, it also inhibits Epstein-Barr virus (EBV) and human herpesvirus 8 (HHV-8). Like GCV, it is phosphorylated by the kinase encoded by UL97. It is more potent in vitro and in vivo than ganciclovir but has a somewhat different pattern of resistance. In one resistant strain, the key mutation formed a stop codon resulting in a truncated pUL97 kinase protein. The phosphorylation of CPV by pUL97 is more efficient than that of GCV, with a considerably lower Km and higher Vmax. Interestingly, the phosphorylation of CPV to its monophosphate (CPV-MP) selleck by pUL97 is stereoselective; only the (+) isomer of CPV-MP is formed. A single enzyme, GMP kinase, phosphorylates CPM-MP to both its di- and triphosphates. In contrast, acyclovir and GCV require additional cellular enzymes to convert their diphosphates to active triphosphates. Cyclopropavir

is currently in Phase I clinical trials for the treatment of HCMV infections. Piet Herdewijn, Rega Institute for Medical Research, KU Leuven, Belgium (Fig. 4). The 2013 ICAR began with a symposium, on the legacy of the late Antonín (Tony) Holý, at which the establishment of a new ISAR award in medicinal chemistry Immune system was announced. The awardee is to be a senior scientist of international stature in medicinal chemistry and who has made innovative contributions impacting antiviral drug discovery or development. Piet is, therefore, the first to receive this award. In the late 1970s, the potent activities of BVDU and BVaraU against herpes simplex virus type 1 (HSV-1) and varicella zoster virus (VZV) were discovered; this work motivated Piet to start antiviral

research with the synthesis of carbocyclic BVDU. Through to the early 1990s, he synthesized several other nucleoside analogs with bicyclic bases having good activity against HSV-1 and VZV. During the 1990s, emphasis switched to investigating the effect of modifying the sugar ring, in particular the synthesis of six-membered rings containing an oxygen or a double bond. Piet showed examples of compounds with activity against HSV-1, HSV-2, VZV and HCMV. Back in 1984, Erik De Clercq showed Piet a paper on AIDS, one of the authors being Phil Furman. This publication stimulated the search for anti-HIV compounds. Many compounds were discovered with potent activities (and good selectivity indices) against HIV. Piet worked out the first structure–activity relationships of anti-HIV dideoxy nucleosides.