Discovery of N-Containing (-)-Borneol Esters as Respiratory Syncytial Virus Fusion Inhibitors

Abstract

Respiratory syncytial virus (RSV) causes acute respiratory infections, thus, posing a serious threat to the health of infants, children, and elderly people. In this study, we have discovered a series of potent RSV entry inhibitors with the (-)-borneol scaffold. The active compounds 3b, 5a, 5c, 7b, 9c, 10b, 10c, and 14b were found to exhibit activity against RSV A strain A2 in НЕр-2 cells. The most active substances, 3b (IC50 = 8.9 μM, SI = 111) and 5a (IC50 = 5.0 μM, SI = 83), displayed more potency than the known antiviral agent Ribavirin (IC50 = 80.0 μM, SI = 50). Time-of-addition assay and temperature shift studies demonstrated that compounds 3b, 5a, and 6b inhibited RSV entry, probably by interacting with the viral F protein that mediated membrane fusion, while they neither bound to G protein nor inhibited RSV attachment to the target cells. Appling procedures of molecular modeling and molecular dynamics, the binding mode of compounds 3b and 5a was proposed. Taken together, the results of this study suggest (-)-borneol esters to be promising lead compounds for developing new anti-RSV agents.

New Inhibitors of Respiratory Syncytial Virus (RSV) Replication Based on Monoterpene-Substituted Arylcoumarins

“…The main objective of the molecular dynamics simulations was to evaluate the behavior of the leader compound within the binding site. The model system was constructed in such a way that the transmembrane domain of the protein was immersed in the membrane [ 8 ].…”

“…Given the structure of the full-length F protein, the transmembrane domain (525–550 a.o.) was placed in the POPC membrane (phosphatidylcholine) [ 8 ]. Phosphatidylcholine is part of most cell membranes of viruses [ 29 , 30 ].…”

“…The F protein is essential for viral entry into the host cell and is considered to be an important target for therapy with low-molecular weight inhibitors, such as JNJ-53718678 [ 6 ] and sisunatovir [ 7 ] ( Figure 1 ), which are under the second phase of clinical trials. Recently, monoterpenoid (–)-borneol and triterpenoid ursolic acid-derived esters 1 [ 8 ] and 2 [ 9 ] have been found to exhibit significant antiviral activity against RSV.…”

Biochemistry of the Respiratory Syncytial Virus L Protein Embedding RNA Polymerase and Capping Activities

“…In this review, we focus on the development of antiviral strategies targeting the L protein, which orchestrate the replication and transcription, and we will only describe the most relevant and recent molecules. Exhaustive references of antivirals and a snapshot of the clinical interventions targeting RSV have been reviewed in (accessed date 9 January 2023) and [ 155 , 156 , 157 , 158 , 159 , 160 , 161 , 162 , 163 , 164 ] ( Figure 8 ). The current approaches to inhibiting the RSV polymerase include nucleoside and non-nucleoside analogs inhibitors that have been identified by screening compounds using infectious RSV, cell-based replicon assays, and in vitro assays that use the recombinant L–P complex and naked RNA as templates.…”

“… Snapshot of the development of RSV clinical interventions. Adapted from the PATH website at (accessed date 9 January 2023) and [ 155 , 156 , 157 , 158 , 159 , 160 , 161 , 162 , 163 , 164 ]. …”