Discovery of Sisunatovir (RV521), an Inhibitor of Respiratory Syncytial Virus Fusion

Abstract

RV521 is an orally bioavailable inhibitor of respiratory syncytial virus (RSV) fusion that was identified after a lead optimization process based upon hits that originated from a physical property directed hit profiling exercise at Reviral. This exercise encompassed collaborations with a number of contract organizations with collaborative medicinal chemistry and virology during the optimization phase in addition to those utilized as the compound proceeded through preclinical and clinical evaluation. RV521 exhibited a mean IC 50 of 1.2 nM against a panel of RSV A and B laboratory strains and clinical isolates with antiviral efficacy in the Balb/C mouse model of RSV infection. Oral bioavailability in preclinical species ranged from 42 to >100% with evidence of highly efficient penetration into lung tissue. In healthy adult human volunteers experimentally infected with RSV, a potent antiviral effect was observed with a significant reduction in viral load and symptoms compared to placebo.

Probing In Silico the Benzimidazole Privileged Scaffold for the Development of Drug-like Anti-RSV Agents

“…Based on the superimposition of the two complexes (RMSD = 1.092 Å), both the two compounds share the same positioning for the indole (JNJ-53718678) and benzimidazole (RV521) main cores, projecting the Cl and aminomethyl substituents toward D489, in accordance with previous observation [28]. The two hydrophobic and flexible chains bearing a sulphone and a trifluoromethyl group were oriented in proximity of F140 and of the cavity delimited by L141, L142, detecting Van der Waals contacts.…”

“…Thus, an efficient RSV fusion inhibitor should provide, as a mandatory prerequisite, adequate interactions with aromatic residues of the target as previously illustrated for the rigid anti-RSV agent BTA-9881 (pdb code = 5EA6) [13], only exhibiting contacts with the key F488 residue. Based on the superimposition of the two complexes (RMSD = 1.092 Å), both the two compounds share the same positioning for the indole (JNJ-53718678) and benzimidazole (RV521) main cores, projecting the Cl and aminomethyl substituents toward D489, in accordance with previous observation [28]. The two hydrophobic and flexible chains bearing a sulphone and a trifluoromethyl group were oriented in proximity of F140 and of the cavity delimited by L141, L142, detecting Van der Waals contacts.…”

“…The effective RSV inhibitor RV521 exhibited a comparable binding mode, folding the two heterocyclic rings to display π-π interaction and hydrophobic contacts with the aforementioned F140 and F488 (Figure S3). Interestingly, the aminomethylene chain at position 5 of the benzimidazole ring highly mimicked the positioning of the 5-Cl atom on the indole ring of JNJ-53718678 [28].…”

“…As shown in Figure 4, the bioactive conformation of RV521 (pdb code = 7KQD) [28] and JNJ-53718678 (pdb code = 5KWW) [27] is compared by the superimposition of the related X-ray crystallographic data within the RSV F protein, respectively.…”

Anno 2021: Which antivirals for the coming decade?

“…3 ) 73 and sisunatovir ( 14 , RV521; ReViral, Fig. 3 ), 74 respectively, which are currently being evaluated for oral administration in hospitalized infants and vulnerable adult populations. Phase II studies are also in progress for ziresovir ( 15 , AK0529; in-licensed by Ark Biosciences from Roche, Fig.…”