Targeting structural features of viral genomes with a nano-sized supramolecular drug

Abstract

RNA targeting is an exciting frontier for drug design. Intriguing targets include functional RNA structures in structurally-conserved untranslated regions (UTRs) of many lethal viruses. However, computational docking screens, valuable in protein structure...

Supramolecular Cylinders Target Bulge Structures in the 5′ UTR of the RNA Genome of SARS‐CoV‐2 and Inhibit Viral Replication**

“…Thec ylinders bind strongly to these structures. [32][33][34]51] Once the cylinder is in the SL5 bulge (Figure 4A, cylinder D), the simulations show that the helical structure of the surrounding stems is disturbed, opening up the stem nucleotides to attack from 1M7, and this is confirmed experimentally in SHAPE leading to an increase in the signal in these regions (around Land Mand towards W, close to the RT primer).…”

“…In the simulations where the cylinders started away from the RNA, they quickly localized ON those hinges, reducing flexibility of the hinge drastically (in regions W, L, N, R). From studies with three base bulges (on HIV TAR) we know that such hinges can open and from such a binding position the cylinder can reorient and insert, though this can take very long on the time scales of simulations; [51] we can model this by pre‐positioning the cylinder at or close to this position. The cylinders bind strongly to these structures [32–34, 51] .…”

“…From studies with three base bulges (on HIV TAR) we know that such hinges can open and from such a binding position the cylinder can reorient and insert, though this can take very long on the time scales of simulations; [51] we can model this by pre‐positioning the cylinder at or close to this position. The cylinders bind strongly to these structures [32–34, 51] . Once the cylinder is in the SL5 bulge (Figure 4 A, cylinder D), the simulations show that the helical structure of the surrounding stems is disturbed, opening up the stem nucleotides to attack from 1M7, and this is confirmed experimentally in SHAPE leading to an increase in the signal in these regions (around L and M and towards W, close to the RT primer).…”

Supramolecular Cylinders Target Bulge Structures in the 5′ UTR of the RNA Genome of SARS‐CoV‐2 and Inhibit Viral Replication**

“…As seen in free SL5, the bulges serve as dynamic hinges giving flexibility to the surrounding stems.Inthe simulations where the cylinders started away from the RNA, they quickly localized ON those hinges,reducing flexibility of the hinge drastically (in regions W, L, N, R). From studies with three base bulges (on HIV TAR) we know that such hinges can open and from such abinding position the cylinder can reorient and insert, though this can take very long on the time scales of simulations; [51] we can model this by pre-positioning the cylinder at or close to this position. Thec ylinders bind strongly to these structures.…”

Infectious RNA: Human Immunodeficiency Virus (HIV) Biology, Therapeutic Intervention, and the Quest for a Vaccine

“…To reduce the propensity of re-emerging drug resistant variants, promising targets for compound-mediated therapeutic interventions could include conserved mRNA structures such as hairpins, stem-loops, and bulges present in TAR [137][138][139][140], RRE [62,141,142], and Psi [143][144][145], as these structurers interact specifically with their cognate viral protein counterparts, namely, Tat, Rev, and the p7-NC of the core protein Gag, respectively. However, these novel approaches are still in the pioneering stage.…”