Publications

We have developed a series of N(2) -(1-(substituted-aryl)piperidin-4-yl)-N(6) -mesityl-9H-purine-2,6-diamine derivatives as potent antiviral agents. Preliminary biological evaluation indicated that nearly half of them possessed remarkable HIV inhibitory potencies in cellular assays. In particular, FZJ13 appeared to be the most notable one, which displayed anti-HIV-1 activity compared to 3TC. Moreover, an unexpected finding was that FZJ05 displayed significant potency against influenza A/H1N1 (strain A/PR/8/34) in Madin-Darby canine kidney cells with EC50 values much lower than those of ribavirin, amantadine, and rimantadine. The results suggest that these novel purine derivatives have the potential to be further developed as new therapeutic agents against HIV-1 or influenza virus.

We have recently discovered bicyclic furopyrimidines as potent and selective inhibitors of VZV. In order to investigate the structural requirements for antiviral activity we have succesfully synthesised some 3'-chloro and 5'-chloro derivatives. The compounds have been tested against VZV and CMV, but displayed no significant in vitro activity.

Acyclovir is a potent and selective antiviral agent. Unfortunately, drug-resistant (acyclovir-resistant) mutants have already been reported in herpes simplex virus type 1 (HSV-1) orofacial infections. We have developed a laboratory acyclovir-resistant HSV-1 mutant. The natural course of acyclovir-resistant HSV-1 keratitis was found to be less virulent than that observed in wild type HSV-1 keratitis, but the rate of ganglionic latency was as high as that induced by the parental strain. In vitro studies and in vivo observation of rabbit corneas infected with acyclovir-resistant HSV-1 both demonstrated a significant sensitivity to vidarabine and bromovinyldeoxyuridine ([E]-5-[2-bromovinyl]-2'-deoxyuridine). The thymidine kinase activity of the acyclovir-resistant mutant was 69% of that of the wild type HSV-1.

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A series of novel N,O-psiconucleosides has been prepared in both enantiomeric forms by resolution of an advanced racemic synthetic intermediate using (R)-N-phenylpantolactam as a chiral resolution agent. The absolute configuration of all of these compounds has been unequivocally established by chemical correlation with the novel (R)- or (S)-1-methyl-5-phenylpyrrolidine-2,3-dione, prepared from the known (R)- and (S)-1-methyl-5-phenylpyrrolidin-2-one, respectively.

During the last forty years we have witnessed impressive advances in the field of antiviral drug discovery culminating with the introduction of therapies able to stop human immunodeficiency virus (HIV) replication, or cure hepatitis C virus infections in people suffering from liver disease. However, there are important viral diseases without effective treatments, and the emergence of drug resistance threatens the efficacy of successful therapies used today. In this review, we discuss strategies to discover antiviral compounds specifically designed to combat drug resistance. Currently, efforts in this field are focused on targeted proteins (e.g. multi-target drug design strategies), but also on drug conformation (either improving drug positioning in the binding pocket or introducing conformational constraints), in the introduction or exploitation of new binding sites, or in strengthening interaction forces through the introduction of multiple hydrogen bonds, covalent binding, halogen bonds, additional van der Waals forces or multivalent binding. Among the new developments, proteolysis targeting chimeras (PROTACs) have emerged as a valid approach taking advantage of intracellular mechanisms involving protein degradation by the ubiquitin-proteasome system. Finally, several molecules targeting host factors (e.g. human dihydroorotate dehydrogenase and DEAD-box polypeptide 3) have been identified as broad-spectrum antiviral compounds. Implementation of herein described medicinal chemistry strategies are expected to contribute to the discovery of new drugs effective against current and future threats due to emerging and re-emerging viral pandemics.

Various nucleoside analogues were examined for their inhibitory effects on plaque formation of the laboratory strain AD-169 and 11 clinical isolates of human cytomegalovirus (CMV) in human embryonic fibroblast (MRC-5) cells. The most selective inhibitors of CMV replication were 9-(1,3-dihydroxy-2-propoxymethyl)guanine (DHPG), (S)-1-(3-hydroxy-2-phosphonylmethoxypropyl)cytosine (HPMPC), and (S)-9-(3-hydroxy-2-phosphonylmethoxypropyl)adenine (HPMPA). The 50% effective concentrations (EC50) for CMV plaque formation were 0.65, 0.25, and 0.28 microgram/ml, respectively. Selectivity indexes were 462, 300, and 107, respectively. At a concentration fourfold higher than the EC50, HPMPC completely inhibited CMV growth, whereas DHPG still allowed it. Carbocyclic 3-deazaadenosine, recognized as an S-adenosylhomocysteine (SAH) hydrolase inhibitor, had an EC50 of 13.7 micrograms/ml and a selectivity index of 29. These results suggest that HPMPC should be further pursued for its usefulness in the treatment of CMV infections and SAH hydrolase inhibitors represent potentially important anti-CMV agents.