title: Bacterial RNase P RNA is a drug target for aminoglycoside-arginine conjugates.
abstract: The ribonuclease P (RNase P) holoenzymes are RNPs composed of RNase P RNA (PRNA) and a variable number of P protein subunits. Primary differences in structure and function between bacterial and eukaryotic RNase P and its indispensability for cell viability make the bacterial enzyme an attractive drug target. On the basis of our previous studies, aminoglycoside-arginine conjugates (AACs) bind to HIV-1 TAR and Rev responsive element (RRE) RNAs significantly more efficiently than neomycin B. Their specific inhibition of bacterial rRNA as well as the findings that the hexa-arginine neomycin derivative (NeoR6) is 500-fold more potent than neomycin B in inhibiting bacterial RNase P, led us to explore the structure-function relationships of AACs in comparison to a new set of aminoglycoside-polyarginine conjugates (APACs). We here present predicted binding modes of AACs and APACs to PRNA. We used a multistep docking approach comprising rigid docking full scans and final refinement of the obtained complexes. Our docking results suggest three possible mechanisms of RNase P inhibition by AACs and APACs: competition with the P protein and pre-tRNA on binding to P1-P4 multihelix junction and to J19/4 region (probably including displacement of Mg2+ ions from the P4 helix) of PRNA; competition with Mg2+ ions near the P15 loop; and competition with the P protein and/or pre-tRNA near the P15 helix and interfering with interactions between the P protein and pre-tRNA at this region. The APACs revealed about 10-fold lower intermolecular energy than AACs, indicating stronger interactions of APACs than AACs with PRNA.
authors: Department of Organic Chemistry, The Weizmann Institute of Science, Rehovot 76100, Israel.
authors: Alexander
authors: A
authors: Berchanski
authors: Aviva
authors: A
authors: Lapidot
mesh_terms: D000465:Algorithms; D000617:Aminoglycosides / Q000737:chemistry / Q000494:pharmacology*; D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000494:pharmacology*; D001120:Arginine / Q000737:chemistry*; D001667:Binding, Competitive; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D005601:Framycetin / Q000494:pharmacology; D015752:Genes, env / Q000502:physiology; D008274:Magnesium / Q000737:chemistry; D012329:RNA, Bacterial / Q000378:metabolism*; D043262:Ribonuclease P / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D000617:Aminoglycosides; D000900:Anti-Bacterial Agents; D004791:Enzyme Inhibitors; D012329:RNA, Bacterial; D005601:Framycetin; D001120:Arginine; D043262:Ribonuclease P; D008274:Magnesium