Antiviral research最新文献

Antiviral drugs are crucial for managing viral infections, but current treatment options remain limited, particularly for emerging viruses. These drugs can be classified based on their chemical composition, including neutralizing antibodies (nAbs), recombinant human receptors (rhRs), antiviral CRISPR/Cas systems, interferons, antiviral peptides (APs), antiviral nucleic acid polymers, and small molecules. Some of these agents target viral factors, host factors, or both. A major challenge for virus-targeted treatments is their narrow-spectrum effectiveness and the potential for drug resistance, while host-directed and virus/host-targeted therapies often suffer from significant side effects. The synergistic combination of multiple antiviral drugs holds promise for improving treatment outcomes by targeting different stages of the viral life cycle, reducing resistance, and minimizing side effects. However, developing such drug combinations presents its own set of challenges. Several drug combinations could be optimized, and new combinations developed by using AI, to more effectively treat both emerging and re-emerging viral infections.

While the COVID-19 crisis is still ongoing, a new public health threat has emerged with recent outbreaks of monkeypox (mpox) infections in Africa. Mass vaccination is not currently recommended by the World Health Organization (WHO), and antiviral treatments are yet to be specifically approved for mpox, although existing FDA-approved drugs (Tecovirimat, Brincidofovir, and Cidofovir) may be used in severe cases or for immunocompromised patients. A first-line of defense is thus drug repurposing, which was heavily attempted against SARS-CoV-2 - albeit with limited success. This review focuses on nucleoside analogues as promising antiviral candidates for targeting of the viral DNA-dependent DNA polymerase. In contrast to broad-spectrum screening approaches employed for SARS-CoV-2, we emphasize the importance of understanding the structural specificity of viral polymerases for rational selection of potential candidates. By comparing DNA-dependent DNA polymerases with other viral polymerases, we highlight the unique features that influence the efficacy and selectivity of nucleoside analogues. These structural insights provide a framework for the preselection, repurposing, optimization, and design of nucleoside analogues, aiming to accelerate the development of targeted antiviral therapies for mpox and other viral infections.

Infection with one or several of the five known hepatitis viruses is a leading cause of liver disease and poses a high risk of developing hepatocellular carcinoma upon chronic infection. Chronicity is primarily caused by hepatitis B virus (HBV) and hepatitis C virus (HCV) and poses a significant health burden worldwide. Co-infection of chronic HBV infected patients with hepatitis D virus (HDV) is less common but is marked as the most severe form of chronic viral hepatitis. Hepatitis A virus (HAV) and hepatitis E virus (HEV) primarily cause self-limiting acute hepatitis. However, studies have also reported chronic progression of HEV disease in immunocompromised patients. While considerable progress has been made in the treatment of HCV and HBV through the development of direct-acting antivirals (DAAs), challenges including drug resistance, incomplete viral suppression resulting in failure to achieve clearance and the lack of effective treatment options for HDV and HEV remain. Host-targeting antivirals (HTAs) have emerged as a promising alternative approach to DAAs and aim to disrupt virus-host interactions by modulating host cell pathways that are hijacked during the viral replication cycle. The aim of this review is to provide a comprehensive overview about the major milestones in research and development of HTAs for chronic HBV/HDV and HCV infections. It also summarizes the current state of knowledge on promising host-targeting therapeutic options against HEV infection.

The Phosphoprotein (P protein) of the rabies virus has multiple roles in virus replication. A critical function is to act as a cofactor in genome replication and mRNA production through binding via its N-terminal region to the L protein, the essential enzyme for mRNA and genome synthesis/processing, and via its C-terminal domain (P_CTD) to the N protein and viral RNA (N-RNA) ribonucleoprotein complex. The binding site of the P_CTD on the N protein is a disordered loop that is expected to be phosphorylated at Ser389. This interface may provide novel targets for antiviral approaches. Following an alanine scan of the peptide we selected two single site mutations that showed improved affinity and combined these mutations with a phosphomimetic (S389E) to produce double and triple mutants in the context of linear and cyclic peptides of the disordered loop, with the goal of generating a competitive peptide against the N-RNA complex. To assess the binding properties of the peptides we characterized their thermodynamics identifying complex properties of improved enthalpy but with compensating entropy for mutants and cyclized peptides. Nevertheless, a triple mutant shows 3.5-fold stronger affinity for P_CTD than the full-length S389E N protein. Structural characterization of the triple mutant suggests the improved affinity may be due to trapping a favoured β-strand structure for binding to the P_CTD. This novel peptide may serve as a template for the future design of antivirals.

The viral NS2B-NS3 protease is a promising drug target to combat dengue virus (DENV) and other emerging flaviviruses. The discovery of novel DENV protease inhibitors with antiviral efficacy is hampered by the low predictive power of biochemical assays. We herein present a comparative evaluation of biochemical DENV protease assay conditions and their benchmarking against antiviral efficacy and a protease-specific reporter gene assay. Variations were performed with respect to pH, type of detergent, buffer, and substrate. The revised assay conditions were applied in a medicinal chemistry effort aimed at phenylglycine protease inhibitors. This validation study demonstrated a considerably improved predictive power for antiviral efficacy in comparison to previous approaches. An extensive evaluation of phenylglycine-based DENV protease inhibitors with highly diverse N-terminal caps indicates further development potential in this structural region. Furthermore, the phenylglycine moiety may be less essential than previously assumed, providing a development option towards reduced lipophilicity and thereby an improved pharmacokinetic and toxicity profile.

The impact of treatment-emergent amino acid substitutions (TEAASs) in SARS-CoV-2 3C-like protease (3CL^pro) on clinical and virologic outcomes was evaluated in patients with mild-to-moderate COVID-19 who received ensitrelvir 125 mg in the SCORPIO-SR trial. Individuals were randomised to ensitrelvir or matched placebo once daily for 5 days (first dose <72 h after disease onset). 3CL^pro-TEAASs were identified by sequencing nsp5 encoding 3CL^pro from pre- and post-treatment nasopharyngeal swabs. Time to resolution of a composite of five characteristic COVID-19 symptoms (TTR) was compared between patients with and without most common 3CL^pro-TEAASs in the ensitrelvir arm. The ensitrelvir and placebo intention-to-treat populations comprised 345 and 341 patients, respectively. 3CL^pro-TEAASs were detected in 19/204 (9.3%) ensitrelvir-treated and 3/137 (2.2%) placebo-treated patients with paired sequence data. The most common 3CL^pro-TEAASs in the ensitrelvir arm were M49L (n=12), M49I (n=3) and S144A (n=2). In the placebo arm, all 3CL^pro-TEAASs occurred in ≤1 patient. Median (95% confidence interval) TTR was comparable between patients with and without those TEAASs (158.8 h [112.1-281.9] vs 189.7 h [151.4-234.4]). Mean viral RNA levels declined more slowly in patients with M49L/I or S144A versus those without. Reductions in viral titre were unaffected by these TEAASs. The characteristics of recombinant SARS-CoV-2 with 3CL^pro mutations were explored in vitro. Recombinant viruses with some 3CL^pro mutations had reduced susceptibility to ensitrelvir in vitro, with limited effects on viral and competitive fitness. Continued surveillance is warranted to monitor the spread of viruses with 3CL^pro mutations.

Viruses have co-evolved with their hosts, intertwining their life cycles. As a result, components and pathways from a host cell's processes are appropriated for virus infection. This review examines the host DExD-box RNA helicases known to influence virus infection during human infections. We have identified 42 species of viruses (28 genera and 21 families) whose life cycles are modulated by at least one, but often multiple, DExD-box RNA helicases. Of these, 37 species require one or multiple DExD-box RNA helicases for efficient infections, i.e., in these cases the DExD-box RNA helicases are pro-viral. However, similar evolutionary processes have also led to cellular responses that combat viral infections. In humans, these responses comprise intrinsic and innate immune reactions initiated and regulated by some of the same DExD-box RNA helicases that act as pro-viral helicases. Currently, anti-viral DExD-box RNA helicase responses to viral infections are noted in 23 viral species. Notably, most studied viruses are linked to severe, life-threatening diseases, leading many researchers to focus on DExD-box RNA helicases as potential therapeutic targets. Thus, we present examples of host-directed therapies targeting anti-viral DExD-box RNA helicases. Overall, our findings indicate that various DExD-box RNA helicases serve as either pro- and/or anti-viral agents across a wide range of viruses. Continued investigation into the pro-viral activities of these helicases will help identify specific protein motifs that can be targeted by drugs to manage or eliminate the severe diseases caused by these viruses. Comparative studies on anti-viral DExD-box RNA helicase responses may also offer insights for developing therapies that enhance immune responses triggered by these helicases.