Biology subjects

Belhaouari, D. B.

Publications and source records attributed to Belhaouari, D. B..

2 recordsLinked to original sources

bioRxiv2025

Discovery and Characterization of a Hydroxypyridone-3-carboxamide Analog as an Antiviral Lead against Orthopoxviruses

Orthopoxviruses remain a persistent global health concern due to the ongoing circulation of mpox, the possibility of the re-emergence of smallpox, and the threats posed by many poxviruses that infect animals and/or humans. The limited availability of antiviral drugs, the unproven efficacy in humans, and the emergence of resistant mutants underscore the need for new and better therapeutics. In this study, we identify and characterize ZW-2038, a hydroxypyridone-3-carboxamide analog, as an antiviral compound against vaccinia virus (VACV), monkeypox virus (MPXV), and cowpox virus (CPXV). Discovered through a focused in-house small-molecule screen, ZW-2038 exhibited low micromolar potency and high selectivity in primary human fibroblasts. The compound also reduced viral replication under physiomimetic conditions including human and monkey intestinal organoids (enteroids) and ex vivo mouse lung tissue models. Mechanistically, ZW-2038 suppresses VACV DNA replication and downstream post-replicative gene expression, albeit without inhibiting MPXV resolvase (Mpr) in vitro. These findings, along with in vitro safety profiling and mice pharmacokinetics studies, characterize ZW-2038 as a promising yet suboptimal antiviral lead against orthopoxviruses warranting future development.

microbiology↗

bioRxiv2025

Ciclopirox suppresses poxvirus replication by targeting iron metabolism

Poxviruses remain a significant global health concern, necessitating the development of novel antiviral strategies. Through high-throughput screening, we previously identified ciclopirox (CPX), an FDA-approved antifungal, as a hit that inhibits vaccinia virus (VACV) replication. Here, we further characterized its antiviral activity and mechanism of action using human primary fibroblasts. CPX significantly reduced VACV titers without reducing host cell viability, with an EC50 in the sub-micromolar range and a CC50 >500 M. Rescue experiments demonstrated that CPX inhibits viral replication primarily through chelation of intracellular Fe3+ and, to a lesser extent, Fe2+, as evidenced by partial restoration of viral replication with ferric ammonium citrate supplementation. Furthermore, overexpression of the iron-dependent enzymes RRM2 and the VACV-encoded F4L reduced the inhibitory effect of CPX, indicating that these host and viral proteins are affected by CPX treatment. Moreover, CPX treatment also suppressed cowpox virus and monkeypox (mpox) virus replication in vitro. It also reduced VACV titers in ex vivo mouse lung tissue. These findings highlight host iron metabolism as a critical determinant of poxvirus replication and support repurposing CPX as a broad-spectrum orthopoxvirus antiviral candidate.

microbiology↗