title: Multivalency in the recognition and antagonism of a HIV TAR RNA-TAT assembly using an aminoglycoside benzimidazole scaffold.
abstract: Recognition of RNA by high-affinity binding small molecules is crucial for expanding existing approaches in RNA recognition, and for the development of novel RNA binding drugs. A novel neomycin dimer benzimidazole conjugate 5 (DPA 83) was synthesized by conjugating a neomycin-dimer with a benzimidazole alkyne using click chemistry to target multiple binding sites on HIV TAR RNA. Ligand 5 significantly enhances the thermal stability of HIV TAR RNA and interacts stoichiometrically with HIV TAR RNA with a low nanomolar affinity. 5 displayed enhanced binding compared to its individual building blocks including the neomycin dimer azide and benzimidazole alkyne. In essence, a high affinity multivalent ligand was designed and synthesized to target HIV TAR RNA.
authors.affiliation: Laboratory of Medicinal Chemistry, Department of Chemistry, Clemson University, Clemson, SC 29634, USA. dparya@clemson.edu.
authors.forename: Sunil
authors.initials: S
authors.lastname: Kumar
authors.affiliation: Laboratory of Medicinal Chemistry, Department of Chemistry, Clemson University, Clemson, SC 29634, USA. dparya@clemson.edu and Nubad LLC, 900 B West Faris Road, Greenville, SC 29630, USA.
authors.forename: Nihar
authors.initials: N
authors.lastname: Ranjan
authors.affiliation: Laboratory of Medicinal Chemistry, Department of Chemistry, Clemson University, Clemson, SC 29634, USA. dparya@clemson.edu.
authors.forename: Patrick
authors.initials: P
authors.lastname: Kellish
authors.affiliation: Laboratory of Medicinal Chemistry, Department of Chemistry, Clemson University, Clemson, SC 29634, USA. dparya@clemson.edu.
authors.forename: Changjun
authors.initials: C
authors.lastname: Gong
authors.affiliation: Nubad LLC, 900 B West Faris Road, Greenville, SC 29630, USA.
authors.forename: Derrick
authors.initials: D
authors.lastname: Watkins
authors.affiliation: Laboratory of Medicinal Chemistry, Department of Chemistry, Clemson University, Clemson, SC 29634, USA. dparya@clemson.edu.
authors.forename: Dev P
authors.initials: DP
authors.lastname: Arya
mesh_terms: D000617:Aminoglycosides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001562:Benzimidazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001665:Binding Sites / Q000187:drug effects; D057930:Click Chemistry; D004305:Dose-Response Relationship, Drug; D016325:HIV Long Terminal Repeat / Q000187:drug effects*; D008024:Ligands; D008968:Molecular Conformation; D009355:Neomycin / Q000737:chemistry / Q000494:pharmacology; D012367:RNA, Viral / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
chemical_list: D000617:Aminoglycosides; D001562:Benzimidazoles; D008024:Ligands; D012367:RNA, Viral; C031000:benzimidazole; D009355:Neomycin