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Abstract Purpose of the ReviewSARS-CoV-2 undergoes genetic mutations like many other viruses. Some mutations lead to the emergence of new Variants of Concern (VOCs), affecting transmissibility, illness severity, and the effectiveness of antiviral drugs. Continuous monitoring and research are crucial to comprehend variant behavior and develop effective response strategies, including identifying mutations that may affect current drug therapies. Recent FindingsAntiviral therapies such as Nirmatrelvir and Ensitrelvir focus on inhibiting 3CLpro, whereas Remdesivir, Favipiravir, and Molnupiravir target nsp12, thereby reducing the viral load. However, the emergence of resistant mutations in 3CLpro and nsp12 could impact the efficiency of these small molecule drug therapeutics. SummaryThis manuscript summarizes mutations in 3CLpro and nsp12, which could potentially reduce the efficacy of drugs. Additionally, it encapsulates recent advancements in small molecule antivirals targeting SARS-CoV-2 viral proteins, including their potential for developing resistance against emerging variants. 

The emergence of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has triggered a global COVID-19 pandemic, challenging healthcare systems worldwide. Effective therapeutic strategies against this novel coronavirus remain limited, underscoring the urgent need for innovative approaches. The present research investigates the potential of cannabis compounds as therapeutic agents against SARS-CoV-2 through their interaction with the virus’s papain-like protease (PLpro) protein, a crucial element in viral replication and immune evasion. Computational methods, including molecular docking and molecular dynamics (MD) simulations, were employed to screen cannabis compounds against PLpro and analyze their binding mechanisms and interaction patterns. The results showed cannabinoids with binding affinities ranging from −6.1 kcal/mol to −4.6 kcal/mol, forming interactions with PLpro. Notably, Cannabigerolic and Cannabidiolic acids exhibited strong binding contacts with critical residues in PLpro’s active region, indicating their potential as viral replication inhibitors. MD simulations revealed the dynamic behavior of cannabinoid–PLpro complexes, highlighting stable binding conformations and conformational changes over time. These findings shed light on the mechanisms underlying cannabis interaction with SARS-CoV-2 PLpro, aiding in the rational design of antiviral therapies. Future research will focus on experimental validation, optimizing binding affinity and selectivity, and preclinical assessments to develop effective treatments against COVID-19. 

The COVID-19 pandemic has emphasized the urgency for effective antiviral therapies against SARS-CoV-2. Targeting the main protease (3CLpro) of the virus has emerged as a promising approach, and nirmatrelvir (PF-07321332), the active component of Pfizer’s oral drug Paxlovid, has demonstrated remarkable clinical efficacy. However, the emergence of resistance mutations poses a challenge to its continued success. In this study, we employed alchemical free energy perturbation (FEP) alanine scanning to identify nirmatrelvir-resistance mutations within SARS-CoV-2 3CLpro. FEP identified several mutations, which were validated through in vitro IC50 experiments and found to result in 8- and 72-fold increases in nirmatrelvir IC50 values. Additionally, we constructed SARS-CoV-2 omicron replicons containing these mutations, and one of the mutants (S144A/E166A) displayed a 20-fold increase in EC50, confirming the role of FEP in identifying drug-resistance mutations. Our findings suggest that FEP can be a valuable tool in proactively monitoring the emergence of resistant strains and guiding the design of future inhibitors with reduced susceptibility to drug resistance. As nirmatrelvir is currently widely used for treating COVID-19, this research has important implications for surveillance efforts and antiviral development 

Abstract SARS-CoV-2, especially B.1.1.529/omicron and its sublineages, continues to mutate to evade monoclonal antibodies and antibodies elicited by vaccination. Affinity-enhanced soluble ACE2 (sACE2) is an alternative strategy that works by binding the SARS-CoV-2 S protein, acting as a ‘decoy’ to block the interaction between the S and human ACE2. Using a computational design strategy, we designed an affinity-enhanced ACE2 decoy,FLIF, that exhibited tight binding to SARS-CoV-2 delta and omicron variants. Our computationally calculated absolute binding free energies (ABFE) between sACE2:SARS-CoV-2 S proteins and their variants showed excellent agreement to binding experiments.FLIFdisplayed robust therapeutic utility against a broad range of SARS-CoV-2 variants and sarbecoviruses, and neutralized omicron BA.5 in vitro and in vivo. Furthermore, we directly compared the in vivo therapeutic efficacy of wild-type ACE2 (non-affinity enhanced ACE2) againstFLIF. A few wild-type sACE2 decoys have shown to be effective against early circulating variants such as Wuhan in vivo. Our data suggest that moving forward, affinity-enhanced ACE2 decoys likeFLIFmay be required to combat evolving SARS-CoV-2 variants. The approach described herein emphasizes how computational methods have become sufficiently accurate for the design of therapeutics against viral protein targets. Affinity-enhanced ACE2 decoys remain highly effective at neutralizing omicron subvariants. 

Here, we synthesized and characterized a novel two-dimensional (2D) conjugated electron donor–acceptor (D-A) copolymer (PBDB-T-Ge), wherein the substituent of triethyl germanium was added to the electron donor unit of the polymer. The Turbo–Grignard reaction was used to implement the group IV element into the polymer, resulting in a yield of 86%. This corresponding polymer, PBDB-T-Ge, exhibited a down-shift in the highest occupied molecular orbital (HOMO) level to −5.45 eV while the lowest unoccupied molecular orbital (LUMO) level was −3.64 eV. The peaks in UV-Vis absorption and the PL emission of PBDB-T-Ge were observed at 484 nm and 615 nm, respectively. 

Abstract We report the synthesis and photophysical characterization of novel halogenated dipyrrolonaphthyridine‐diones (X₂–DPNDs, X = Cl, Br, and I), as candidates for photodynamic therapy (PDT) application. Apart from the heavy atom‐induced spin‐orbit coupling (SOC) dynamics in the investigated X₂–DPNDs, it was found that the position of the halogen atom (relative to the nitrogen of the pyrrole ring) also influenced the triplet excited state behavior. Interestingly, the faster/efficiency sensitization of³O₂to¹O₂using X₂–DPND correlates with the rate of triplet population,k_ISC >1.6 × 10⁸s⁻¹for I₂–DPNDvs k_ISC >2.9 × 10⁹s⁻¹for Cl₂–DPND and Br₂–DPND (whereτ_ISC = 343 ± 3 ps for I₂–DPND andτ_ISC = 5–6 ns for Cl₂–DPND and Br₂–DPND are the lowest time constants/values for ISC). Furthermore, the heavy atom‐induced SOC in Cl₂–DPND and Br₂–DPND did not lead to a reduction of the corresponding fluorescence (ca75%vs67% for the parent DPND). The attractive photophysical characteristics of Cl₂/Br₂–DPND put them on the landscape as not only promising PDT agents but also as fluorescence probes. The present study is a stepping stone in the development of novel organic photosystems for synergistic photomedicinal applications.