By analyzing almost 120 000 dinucleotides in over 2000 nonredundant nucleic acid crystal structures, we define 96+1 diNucleotide Conformers, NtCs, which describe the geometry of RNA and DNA dinucleotides. NtC classes are grouped into 15 codes of the structural alphabet CANA (Conformational Alphabet of Nucleic Acids) to simplify symbolic annotation of the prominent structural features of NAs and their intuitive graphical display. The search for nontrivial patterns of NtCs resulted in the identification of several types of RNA loops, some of them observed for the first time. Over 30% of the nearly six million dinucleotides in the PDB cannot be assigned to any NtC class but we demonstrate that up to a half of them can be re-refined with the help of proper refinement targets. A statistical analysis of the preferences of NtCs and CANA codes for the 16 dinucleotide sequences showed that neither the NtC class AA00, which forms the scaffold of RNA structures, nor BB00, the DNA most populated class, are sequence neutral but their distributions are significantly biased. The reported automated assignment of the NtC classes and CANA codes available at dnatco.org provides a powerful tool for unbiased analysis of nucleic acid structures by structural and molecular biologists.
- MeSH
- Biocatalysis MeSH
- DNA chemistry classification MeSH
- Nucleic Acid Conformation * MeSH
- Nucleotide Motifs * MeSH
- Nucleotides chemistry classification MeSH
- Reproducibility of Results MeSH
- Riboswitch MeSH
- Ribosomes chemistry metabolism MeSH
- RNA, Catalytic chemistry metabolism MeSH
- RNA chemistry classification MeSH
- Binding Sites MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
Acyclic nucleoside phosphonates (ANPs) are a recognized class of antiviral and anticancer agents. Since the discovery of ANPs in the mid-1980s, ANPs have gained recognition in pharmaceutical research. Approvals of cidofovir (Vistide®) in 1996 and especially of tenofovir (disoproxyl fumarate, Viread®) in 2001 were important milestones in research of ANPs. It became clear that this class of antivirals has a full potential for the use in human medicine. The biological activity of ANPs is not restricted to antiviral and anticancer effects. This review highlights novel types of ANPs with antimalarial properties. The malarial parasites Plasmodium falciparum (Pf) and P. vivax (Pv) lack de novo pathway for synthesis of purine bases and rely on a salvage pathway enzyme, hypoxanthineguanine-( xanthine) phosphoribosyltransferase (HG(X)PRT) for the synthesis of 6-oxopurine nucleoside monophosphates. Specific ANPs can act as analogues of the enzymatic reaction products. They inhibit PfHGXPRT and/or PvHGPRT and show an antiplasmodial activity in vitro. In particular aza-ANP and bisphosphonate analogues were shown to become promising potential antimalarials.
- Keywords
- 6-oxopurinfosforibosyltransferasa,
- MeSH
- Antimalarials * pharmacokinetics pharmacology chemistry classification therapeutic use MeSH
- Antiviral Agents pharmacokinetics pharmacology chemistry classification therapeutic use MeSH
- Enzyme Inhibitors therapeutic use MeSH
- Humans MeSH
- Malaria * drug therapy MeSH
- Nucleotides pharmacokinetics pharmacology chemistry classification therapeutic use MeSH
- Pentosyltransferases pharmacokinetics pharmacology chemistry therapeutic use MeSH
- Plasmodium drug effects MeSH
- Prodrugs MeSH
- Check Tag
- Humans MeSH
- Publication type
- Research Support, Non-U.S. Gov't MeSH
