Enantioselective Effect of Chiral Small Molecules in SARS-CoV-2 Vaccine-Induced Immune Response.

Although numerous chiral small molecules have been discovered and synthesized, the investigation on their enantioselective immunological effects remains limited. In this study, we designed and synthesized a pair of small molecule enantiomers (R/S-ResP) by covalently bonding two immunostimulators (resiquimod/Res) onto a planar chiral framework (paracyclophane/P). Notably, we found that S-ResP exhibits a 4.05-fold higher affinity for toll-like receptor 7 (TLR7) than R-ResP, thereby more effectively enhancing the functions of dendritic cells and macrophages in cytokine secretion and antigen internalization. Furthermore, we observed that S-ResP significantly enhances RBD antigen-induced cross-neutralization against various SARS-CoV-2 strains compared to R-ResP. These findings demonstrate the enantioselective effects of small molecules on regulating vaccine-induced immune responses and emphasize the significance of chirality in designing small molecular adjuvants.

Single-chirality of single-walled carbon nanotubes (SWCNTs) through chromatography and its potential biological applications

The separation of highly pure single-chirality single-walled carbon nanotubes (SWCNTs) is challenging and also in demand due to their intrinsic physical, optical, and electronic properties. The use of single-chirality and their performance characteristics makes them a selective candidate for multifunctional applications and opens a new front in nanotube development. It has previously been reported that SWCNTs can be separated in various ways by employing direct control and post-synthesis approaches. Herein, we review the separation of single-chiralities of SWCNTs on account of simplicity and time/cost effectiveness by using gel chromatography. The most recent progress in the controlled synthesis of SWCNTs is comprehensively reviewed in terms of selective-diameter, single-chirality, and specific geometric shape. The method to achieve the single-chirality of SWCNTs is also highlighted. Besides addressing COVID-19 characteristics, epidemiology, and pathology, we also review the most recent developments in nano-biosensors for the rapid and early detection of COVID-19. Furthermore, the photothermal/bioimaging response of single-chirality is reviewed in order to enhance the cytotoxicity of drugs against cancer cells over simple carbon nanotubes (CNTs). The single-chirality allows for precise imaging (due to efficient absorption and emission) of tumors/blood vessels up to ~10-fold higher by injecting a low dose. We hope this review stimulates further study on single-chirality controlled SWCNTs for practical applications. Copyright © 2023 The Royal Society of Chemistry.

A molecular dynamic investigation of human rhinovirus 3c protease drug target: insights towards the design of potential inhibitors

The 3C protease is distinguished from most proteases due to the presence of cysteine nucleophile that plays an essential role in viral replication. This peculiar structure encompassed with its role in viral replication has promoted 3C protease as an interesting target for therapeutic agents in the treatment of diseases caused by human rhinovirus (HRV). However, the molecular mechanisms surrounding the chirality of inhibitors of HRV 3C protease remain unresolved. Herein using in silico techniques such molecular dynamic simulation and binding free estimations via molecular mechanics poisson-boltzmann surface area (MM/PBSA), we present a comprehensive molecular dynamics study of the comparison of two potent inhibitors, SG85 and rupintrivir, complexed with HRV3C protease. The binding free energy studies revealed a higher binding affinity for SG85 of 58.853 kcal/mol than that for rupintrivir of 54.0873 kcal/mol and this was found to be in correlation with the experimental data. The energy decomposition analysis showed that residues Leu 127, Thr 142, Ser 144, Gly 145, Tyr 146, Cys 147, His 161, Val 162, Gly 163, Gly 164, Asn 165, and Phe 170 largely contributed to the binding of SG85, whereas His 40, Leu 127, and Gly 163 impacted the binding of rupintrivir. The results further showed that His 40, Glu 71, Leu 127, Cys 147, Gly 163, and Gyl 164 were crucial residues that played a key role in ligand-enzyme binding, and amongst these crucial residues, His 40, Glu 71, and Cys 147 appeared to be conserved in the active site of HRV-3C protease when bound by both inhibitors. These findings provided a comprehensive understanding of the dynamics and structural features and would serve as guidance in the design and development of potent novel inhibitors of HRV.

Effect of nelfinavir stereoisomers on coronavirus main protease: Molecular docking, molecular dynamics simulation and MM/GBSA study.

In this study, the binding strength of 32 diastereomers of nelfinavir, a proposed drug for the treatment of COVID-19, was considered against main protease. Molecular docking was used to determine the most potent diastereomers. The top three diastereomers along with apo form of protein were then considered via molecular dynamics simulation and MM-GBSA method. During the simulation, the structural consideration of four proteins considered was carried out using RMSD, RMSF, Rg and hydrogen bond analysis tools. Our data demonstrated that the effect of nelfinavir RSRSR stereoisomer on protein stability and compactness is higher than the other. We also found from the hydrogen bond analysis that this important diastereomer form three hydrogen bonds with the residues of Glu166, Gly143 and Hie41. MM/GBSA analysis showed that the binding strength of RSRSR is more than other stereoisomers and that the main contributions to binding energy are vdW and electronic terms. The nelfinavir RSRSR stereoisomer introduced in this study may be effective in the treatment of COVID-19.