The Indispensable Value of Small-Molecule Antivirals in Epidemic and Pandemic Preparedness.

Harbingers of infectious viral pandemics, such as the H1N1 influenza, SARS, Zika, Ebola, MERS, and SARS-CoV-2, caused major outbreaks in the first two decades of the 21st century. Despite warnings, therapeutic tools that could be rapidly and sustainably scaled at a global level when SARS-CoV-2 emerged were lacking. Small-molecule antivirals can play a crucial role in both individual patient care and broader public health strategies for controlling and mitigating the impact of viral diseases.

The multifaceted role of the viral 2A protease in enterovirus replication and antagonism of host antiviral responses.

Enteroviruses dramatically remodel the cellular infrastructure for efficient replication and curtailing host antiviral responses. The roles of viral proteins in these processes have been studied mostly in vitro, by ectopic overexpression, or by surrogate infection systems, all of which have shortcomings. Here, we replace the essential 2A cleavage site at the P1-P2 junction with an internal ribosome entry site (IRES), 3CD cleavage site, or T2A sequence, allowing us to catalytically inactivate 2Apro in the virus context.

Antiviral activities of phenylalanine derivatives carrying carboxylic acid bioisosteres against chikungunya and parainfluenza virus type 3.

Pathogenic RNA viruses from various virus families represent substantial public health hazards. Specific antiviral drugs effective against most RNA virus infections have not yet been developed. In this study, it was aimed to investigate the broad-spectrum antiviral activities of phenylalanine derivatives designed by replacing the carboxylic acid moiety with various bioisosteres such as nitrile, hydroxamidine and 5-oxo/thioxo-1,2,4-oxadiazole.

High-throughput split-GFP antiviral screening assay against fusogenic paramyxoviruses.

The paramyxovirus family includes important pathogens such as measles and mumps viruses, as well as emerging pathogens with pandemic potential such as Nipah virus. Despite the threat to public health and the frequent identification of novel paramyxoviruses, no antiviral drugs are currently available. A hallmark of most paramyxoviruses is the induction of cell-cell fusion leading to syncytia formation.

Open-science discovery of DNDI-6510, a compound that addresses genotoxic and metabolic liabilities of the COVID Moonshot SARS-CoV-2 Mpro lead inhibitor.

The 2020 SARS-CoV-2 coronavirus pandemic highlighted the urgent need for novel small molecule antiviral drugs. (S)- DNDI-6510 is a non-covalent SARS-CoV-2 main protease inhibitor developed by the open science collaboration COVID Moonshot. Here, we report on the metabolic and toxicologic optimization of the lead series previously disclosed by the COVID Moonshot Initiative, leading up to the selection of (S)- DNDI-6510 as the preclinical candidate.

Discovery of orally bioavailable Zika and West Nile Virus antiviral compounds targeting the NS2B-NS3 protease.

Flaviviruses are a class of pathogenic viruses with pandemic potential which are typically transmitted via infected arthropods. In particular, Zika virus is sexually transmissible and causes congenital malformations if infection occurs during pregnancy. Although over 1.

PIP4K2C inhibition reverses autophagic flux impairment induced by SARS-CoV-2.

In search for broad-spectrum antivirals, we discover a small molecule inhibitor, RMC-113, that potently suppresses the replication of multiple RNA viruses including SARS-CoV-2 in human lung organoids. We demonstrate selective inhibition of the lipid kinases PIP4K2C and PIKfyve by RMC-113 and target engagement by its clickable analog. Lipidomics analysis reveals alteration of SARS-CoV-2-induced phosphoinositide signature by RMC-113 and links its antiviral effect with functional PIP4K2C and PIKfyve inhibition.

Meeting report: 38th international conference on antiviral research in Las Vegas, United States of America, March 17-21, 2025.

The 38th International Conference on Antiviral Research (ICAR), sponsored by the International Society for Antiviral Research (ISAR), took place March 17-21, 2025 in Las Vegas, Nevada, USA. The annual meeting brought together leading scientists from across academia, industry, and government to present the latest advances in antiviral research. Topics included discovery and development of novel antiviral agents, innovative therapeutic approaches, vaccine technologies, host-targeted strategies, and responses to emerging and re-emerging viral threats.

Discovery and Preclinical Profile of ALG-097558, a Pan-Coronavirus 3CLpro Inhibitor.

The SARS-CoV-2 outbreak of 2019 had a devastating impact on global health and economies worldwide. The viral cysteine protease (3CLpro) is responsible for viral polypeptide bond cleavages and is therefore an essential target to inhibit viral replication. Here, we report the discovery of an orally available, reversible covalent inhibitor of the SARS-CoV-2 main protease that is also highly active across other human coronaviruses and demonstrated oral efficacy in a Syrian hamster infection model at low plasma concentrations.

Discovery of Small Molecules Targeting Norovirus 3CL Protease by Multi-Stage Virtual Screening.

Human noroviruses (HuNoVs) are the primary cause of acute viral gastroenteritis. There are no antivirals or vaccines available to treat and/or prevent HuNoV. Norovirus 3C-like protease (3CLpro) is essential for viral replication; consequently, the inhibition of this enzyme is a fruitful avenue for antinorovirus therapeutics.

Ultrapotent SARS coronavirus-neutralizing single-domain antibodies that clamp the spike at its base.

Therapeutic monoclonal antibodies can prevent severe disease in SARS-CoV-2 exposed individuals. However, currently circulating virus variants have evolved to gain significant resistance to nearly all neutralizing human immune system-derived therapeutic monoclonal antibodies that had previously been emergency-authorized for use in the clinic. Here, we describe the discovery of a panel of single-domain antibodies (VHHs) directed against the spike protein S2 subunit that broadly neutralize SARS-CoV-1 and -2 with unusually high potency.

Functional humoral response during intranasal convalescent plasma prophylaxis for SARS-CoV-2.

Background: The coronavirus disease 2019 (COVID-19) pandemic has had a profound global impact. Therapeutic strategies to bridge the crucial 'lockdown' timespan between the emergence of a new virus and vaccine rollout are needed.

Methods: We recently demonstrated that intranasal (i.

Combinations of approved oral nucleoside analogues confer potent suppression of alphaviruses in vitro and in vivo.

Alphaviruses, including chikungunya virus (CHIKV), pose a significant global health threat, yet specific antiviral therapies remain unavailable. We evaluated combinations of three oral directly acting antiviral drugs (sofosbuvir (SOF), molnupiravir (MPV), and favipiravir (FAV)), which are approved for other indications, against CHIKV, Semliki Forest virus (SFV), Sindbis virus (SINV), and Venezuelan Equine Encephalitis virus (VEEV) in vitro and in vivo. We assessed antiviral efficacy in human skin fibroblasts and liver cells, as well as in a mouse model of CHIKV-induced arthritis.

6-Chlorocoumarin Conjugates with Nucleobases and Nucleosides as Potent Anti-Hepatitis C Virus Agents.

On the basis of a "chemo-combination strategy", (6-chloro)coumarin was incorporated to purines and pyrimidines, as well as their corresponding nucleosides, with a -SCH- linker at different positions under alkaline conditions. These conjugates were found to exert an antiviral effect on the 1b subgenomic replicon replication of the hepatitis C virus (HCV) in Huh 5-2 and Huh 9-13 cells. In this compound library containing 14 new compounds, 6-[(6'-chlorocoumarin-3'-yl)methylthio]purine, 6-(6'-chlorocoumarin-3'-yl)methylthio-9-(β-D-ribofuranos-1″-yl)purine, and 2-[(6'-chlorocoumarin-3'-yl)methylthio]uracil showed great inhibitory abilities, with EC values between 6.

A coronavirus assembly inhibitor that targets the viral membrane protein.

The coronavirus membrane protein (M) is the main organizer of coronavirus assembly. Here, we report on an M-targeting molecule, CIM-834, that blocks the assembly of SARS-CoV-2. CIM-834 was obtained through high-throughput phenotypic antiviral screening followed by medicinal-chemistry efforts and target elucidation.

A small-molecule SARS-CoV-2 inhibitor targeting the membrane protein.

The membrane (M) protein of betacoronaviruses is well conserved and has a key role in viral assembly. Here we describe the identification of JNJ-9676, a small-molecule inhibitor targeting the coronavirus M protein. JNJ-9676 demonstrates in vitro nanomolar antiviral activity against SARS-CoV-2, SARS-CoV and sarbecovirus strains from bat and pangolin zoonotic origin.

The Combination of GS-441524 (Remdesivir) and Ribavirin Results in a Potent Antiviral Effect Against Human Parainfluenza Virus 3 Infection in Human Airway Epithelial Cell Cultures and in a Mouse Infection Model.

Human parainfluenza virus type 3 (HPIV-3) can cause severe respiratory diseases, particularly in young children, the elderly and immunocompromised. There are no approved antiviral drugs against this virus. We report that the combination of ribavirin with either remdesivir or its parent nucleoside GS-441524 results in a pronounced antiviral effect against HPIV-3 in LLC-MK2 cells and in human airway epithelial cells grown at the air-liquid interface.

Combinations of approved oral nucleoside analogues confer potent suppression of alphaviruses and .

Background: Alphaviruses, including chikungunya virus (CHIKV), pose a significant global health threat, yet specific antiviral therapies remain unavailable.

Methods: We evaluated combinations of three oral directly acting antiviral drugs (sofosbuvir (SOF), molnupiravir (MPV), and favipiravir (FAV)), which are approved for other indications, against CHIKV, Semliki Forest virus (SFV), Sindbis virus (SINV), and Venezuelan Equine Encephalitis virus (VEEV) and . We assessed antiviral efficacy in human skin fibroblasts and liver cells, as well as in a mouse model of CHIKV-induced arthritis.

The Dissemination of Rift Valley Fever Virus to the Eye and Sensory Neurons of Zebrafish Larvae Is Stat1-Dependent.

The Rift Valley fever virus (RVFV) causes haemorrhagic fever, encephalitis, and permanent blindness and has been listed by the WHO as a priority pathogen. To study RVFV pathogenesis and identify small-molecule antivirals, we established a novel In Vivo model using zebrafish larvae. Pericardial injection of RVFV resulted in ~4 log viral RNA copies/larva, which was inhibited by the antiviral 2'-fluoro-2'-deoxycytidine.

Optimization of SARS-CoV-2 M Inhibitors by a Structure-Based Multilevel Virtual Screening Method.

With the aim of developing novel anti-SARS-CoV-2 drugs to address the ongoing evolution and emergence of drug-resistant strains, the reported SARS-CoV-2 M inhibitor was selected as a lead to find novel, highly potent, and broad-spectrum inhibitors. Using a fragment-based multilevel virtual screening strategy, 15 hit compounds were identified and subsequently synthesized. Among them, (IC = 1.

Structure-Based Optimization of Pyridone α-Ketoamides as Inhibitors of the SARS-CoV-2 Main Protease.

The main protease M is a clinically validated target to treat infections by the coronavirus SARS-CoV-2. Among the first reported M inhibitors was the peptidomimetic α-ketoamide , whose cocrystal structure with M paved the way for multiple lead-finding studies. We established structure-activity relationships for the series by modifying residues at the P1', P3, and P4 sites.

Antigenic Imprinting Dominates Humoral Responses to New Variants of SARS-CoV-2 in a Hamster Model of COVID-19.

The emergence of SARS-CoV-2 variants escaping immunity challenges the efficacy of current vaccines. Here, we investigated humoral recall responses and vaccine-mediated protection in Syrian hamsters immunized with the third-generation Comirnaty Omicron XBB.1.

Epidemic Zika virus strains from the Asian lineage induce an attenuated fetal brain pathogenicity.

The 2015-2016 Zika virus (ZIKV) outbreak in the Americas revealed the ability of ZIKV from the Asian lineage to cause birth defects, generically called congenital Zika syndrome (CZS). Notwithstanding the long circulation history of Asian ZIKV, no ZIKV-associated CZS cases were reported prior to the outbreaks in French Polynesia (2013) and Brazil (2015). Whether the sudden emergence of CZS resulted from an evolutionary event of Asian ZIKV has remained unclear.

Transcriptional profiling of zebrafish intestines identifies macrophages as host cells for human norovirus infection.

Human noroviruses (HuNoVs) are a major cause of diarrheal disease, yet critical aspects of their biology, including cellular tropism, remain unclear. Although research has traditionally focused on the intestinal epithelium, the hypothesis that HuNoV infects macrophages has been recurrently discussed and is investigated here using a zebrafish larval model. Through single-cell RNA sequencing of dissected zebrafish intestines, we unbiasedly identified macrophages as host cells for HuNoV replication, with all three open reading frames mapped to individual macrophages.