Projects

Systematic SAR studies are performed to identify novel types of antivirals, in particular compounds active against the resistant mutants that are insensitive to commonly used drugs. The aim of the project is also development of potential drug candidates for so far poorly treatable viral diseases (e.g. HIV, HCV). Activity of acyclic nucleoside phosphonates (ANPs) where the nucleobase is attached to a phosphonate moiety via a linker is based on structural similarity with naturally occurring metabolites. ANPs are excellent lead structures for drug design because of the high flexibility, absence of a labile glycosidic bond and enzymatic and chemical stability of the phosphonate moiety compared with the phosphate ester group. They can be transformed to pro-drugs to improve their pharmacological properties and to increase their ability to cross cell membranes and/or target the drug to specific tissue. Effects of various structural alterations of the nucleobase and linker on biological activity and toxicity are studied. The investigation of broad spectrum antiviral activities is performed in collaboration with Rega Institute, Katholic University Leuven (Belgium) and with Gilead Sciences (USA).

The purine salvage enzyme hypoxanthine-guanine-xanthine phosphoribosyltransferase (HGXPRT) is essential for purine mononucleotides synthesis in malaria parasite Plasmodium falciparum (Pf). Humans possess two metabolic pathways, de novo and salvage, and hence are less reliant on the purine salvage pathway for survival. This provides a rationale for the design of inhibitors of PfHGXPRT which will arrest parasitemia and not be toxic to the human host. Acyclic nucleoside phosphonates (ANPs) are structural analogs of the nucleotide product of the enzyme reaction. Our aim is to design ANPs containing a purine base linked by various acyclic chains to a phosphonate group as potent and selective inhibitors of PfHGXPRT and antimalarial drug leads. The investigation of inhibitory activity of targeted ANPs is performed in collaboration with the laboratory of Dr. Luke W. Guddat, University of Queensland, Brisbane (Australia).

Immunomodulating agents
The high-output nitric oxide (NO) production depends largely on the cytokine-mediated activation of inducible NO synthase (iNOS). Measurement of NO production is used as a convenient screening approach. Some of the acyclic nucleoside phosphonates are known iNOS activators with in vitro and in vivo immunomodulatory activity. Our study, in collaboration with the Institute of Experimental Medicine (Academy of Sciences, Prague), is focused on the effect of structure modifications of ANPs and related compounds on cytokine production.

Inhibitors of Toxoplasma gondii S-adenosyl-L-homocysteine hydrolase
Toxoplasma gondii is two-host intracelular parasite with cats as a definitive host. Aabout 1/3 of human population is infected by toxoplasmosis worldwide. Enzyme S-adenosyl-L-homocysteine hydrolase (SAHH) regulating methionine cycle is studied as potential drug target for new antiparasitic drug development. The competitive inhibitor of human SAHH used as an antiherpetic drug, S-dihydroxypropyladenine ((S)-DHPA), was discovered in the group of Prof. A. Holý. Project dealing with nucleoside analogues derived from DHPA should elucidate the differences in the interactions at the substrate binding site between the host and parasite form of SAHH and identify new selective SAHH inhibitors in collaboration with Department of Tropical Medicine (1st Faculty of Medicine of Charles University, Prague) and National Reference Laboratory for Toxoplasmosis (Prague).

Inhibitors of Mycobacterium tuberculosis thymidylate kinase
Mycobacterium tuberculosis thymidylate kinase (TMPKmt) is an attractive target for novel antituberculosis agents. It catalyzes the conversion of dTMP to dTDP, using ATP as its preferred phosphoryl donor. In the frame of the new project with biochemical groups of IOCB we are in quest of potent TMPKmt inhibitors, based on analogs of nucleic acid components, as leading structures for further optimization.