Abstract The persistent threat of influenza pandemics and seasonal outbreaks, coupled with rising resistance to existing antiviral drugs targeting influenza viruses, necessitates the development of new therapeutics. This study investigated the antiviral potential of cell-penetrating peptide–conjugated host nucleolin (NCL)-binding peptide drugs, AGM-380d (dimeric) and AGM-380t (tetrameric), as innovative, broad-spectrum host-directed anti-influenza therapies. Infection with both influenza A and B viruses (IAVs and IBVs) significantly increased NCL expression and colocalization with viral nucleoprotein (NP), a core component of viral ribonucleoprotein complexes, in both in vitro and in vivo settings. The peptide drugs rapidly localized to the nucleolus and specifically bound to NCL. This targeted binding successfully disrupted the interaction between NCL and the NP of IAV and IBV, effectively blocking nuclear NP trafficking and inhibiting the replication of both pandemic and seasonal strains. Importantly, AGM-380d and AGM-380t protected mice from lethal IAV challenge by markedly reducing lung viral replication and pathology. The combination of AGM-380t with oseltamivir resulted in 100% protection from mortality following the deadly IAV challenge. In conclusion, AGM-380d and AGM-380t are highly promising as novel, broad-spectrum host-directed antivirals for the management of seasonal and pandemic influenza.
Thu Ha Nguyen, Muhammad Sharif, Jae-hyun Kim et al.· PNAS Nexus· 0 citations
Trehalose-6-phosphate (T6P) homeostasis is a critical determinant of pathogen survival, positioning T6P phosphatase (TPP) as a high-priority antimicrobial target. Despite its significance, the development of universal TPP inhibitors has remained elusive. Here, we report the biochemical and structural characterization of Dermatophilus congolensis TPP (Dcon-TPP), which reveals a moderate catalytic turnover consistent with other bacterial orthologs. Our 2.9 Å crystal structure uncovers an unprecedented wide-open conformation in a state of functional disassembly, with the catalytic machinery sequestered across a ∼26 Å spatial gap. Comparative analysis reveals a remarkable ∼40 Å trajectory and 79° global rotation of the cap domain-the largest conformational rearrangement reported for the HAD superfamily to date. Our structure reveals that this extreme plasticity is linked to structural instability within the β8-strand, which likely acts as a mechanical latch to enable massive domain sweeps via a lever-arm mechanism. This inherent flexibility imposes a substantial entropic penalty on active-site pre-organization, providing a structural rationale for the modest catalytic efficiency shared by Group 3 TPPs. By elucidating this unique molecular switch, our findings suggest a cryptic allosteric site that can be targeted to lock the enzyme in an inert state, offering a promising strategy to overcome long-standing challenges in TPP inhibitor design.
San Kim, Karthik Rajan Rajamanickam, Han-Gyeol Woo et al.· Biochemical and Biophysical...· 0 citations
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