Strategies for recognition of stem-loop RNA structures by synthetic ligands: application to the HIV-1 frameshift stimulatory sequence.
Production of the Gag-Pol polyprotein in human immunodeficiency virus (HIV) requires a -1 ribosomal frameshift, which is directed by a highly conserved RNA stem-loop. Building on our discovery of a set of disulfide-containing peptides that bind this RNA, we describe medicinal chemistry efforts designed to begin to understand the structure-activity relationships and RNA sequence-selectivity relationships associated with these compounds. Additionally, we have prepared analogues incorporating an olefin or saturated hydrocarbon bioisostere of the disulfide moiety, as a first step toward enhancing biostability. The olefin-containing compounds exhibit affinity comparable to the lead disulfide and, importantly, have no discernible toxicity when incubated with human fibroblasts at concentrations up to 1 mM.
Palde
Prakash B
PB
Department of Dermatology, University of Rochester, Rochester, NY 14642, USA.
Ofori
Leslie O
LO
Gareiss
Peter C
PC
Lerea
Jaclyn
J
Miller
Benjamin L
BL
D000475:Alkenes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D019380:Anti-HIV Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D001483:Base Sequence; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004220:Disulfides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects; D018965:Frameshifting, Ribosomal; D015497:HIV-1 / Q000235:genetics*; D006801:Humans; D008024:Ligands; D009154:Mutation; D009690:Nucleic Acid Conformation; D009841:Oligonucleotides / Q000737:chemistry; D009842:Oligopeptides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D011804:Quinolines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D012367:RNA, Viral / Q000235:genetics*; D013329:Structure-Activity Relationship
D000475:Alkenes; D019380:Anti-HIV Agents; D004220:Disulfides; D008024:Ligands; D009841:Oligonucleotides; D009842:Oligopeptides; D011804:Quinolines; D012367:RNA, Viral