# Host-directed peptide counters flu in preclinical study - bioworld.com

*Источник: bioworld.com*
*Дата: 2026-09-22*
*Язык: en*

**Кратко:** A host-directed peptide antiviral showed broad preclinical activity against influenza, offering proof of concept for targeting a host protein rather than the virus itself. 1, 2026, AGM-380, a nucleolin (NCL)-targeted peptide therapy, protected mice against otherwise lethal influenza in both dimeric (AGM-380d) and tetrameric forms (AGM-380t).

A host-directed peptide antiviral showed broad preclinical activity against influenza, offering proof of concept for targeting a host protein rather than the virus itself.
According to findings published in PNAS Nexus Sept. 1, 2026, AGM-380, a nucleolin (NCL)-targeted peptide therapy, protected mice against otherwise lethal influenza in both dimeric (AGM-380d) and tetrameric forms (AGM-380t). When combined with oseltamivir, marketed as Tamiflu, AGM-380t showed 100% protection from mortality in mice following a lethal influenza A virus (IAV) challenge.
The host-directed flu therapy study, penned by Thu Ha Nguyen, Cho Kyoung-oh and colleagues, presents a novel approach to the cat-and-mouse game of rapidly mutating viral proteins. The findings come amid continuing vulnerabilities in the public health sector against drug-resistant flu strains and zoonotic viruses, which remain under addressed by small-molecule drugs such as oseltamivir, zanamivir, peramivir and baloxavir.
Rapid mutations are common across influenza and zoonotic viruses, including SARS-CoV-2 and highly pathogenic avian influenza H5N1 viruses in dairy cattle and farmed mink. While vaccines for COVID-19 and influenza exist, they must be updated periodically to match newer circulating variants.
Influenza antivirals remain limited to small-molecule drugs; however, the work points to a “compelling strategy” of peptide antivirals to overcome drug resistance and improve influenza management worldwide, the researchers said. “As the efficacy of current influenza therapies is increasingly compromised by the rapid evolution of resistance among circulating strains, developing host-directed therapeutics has become a critical priority.”
AGM-380 belongs to a peptide-based pipeline developed by HLB Pep Co. Ltd., formerly Anygen Co. Ltd., which also produces peptide active pharmaceutical ingredients. The Gwangju-based company has been co-developing AGM-380 with HLB Science Inc., of Seoul, since August 2025. Both are affiliates of Korea’s HLB Group.
HLB Pep previously reported preclinical data for AGM-380 in March 2023, according to Cortellis, which demonstrated antiviral efficacy in infected cells and animal models of influenza A, porcine epidemic diarrhea virus and COVID-19.
Cho is CEO of Gwangju-based Pharmacolinx Inc. and director of the Host-Directed Antiviral Research Center at Chonnam National University. Co-author Kim Jae-il, professor at Gwangju Institute of Science and Technology’s School of Life Sciences, is co-CEO of HLB Pep along with Shim Kyoung-jae. The researchers did not respond to BioWorld’s requests in time for publication.
Securing the server, not the hijacker
“Current antivirals, such as neuraminidase inhibitors, face diminishing efficacy due to mutation-driven resistance, necessitating novel treatment strategies,” Kim and colleagues wrote.
AGM-380d and AGM-380t are designed to intervene early in the viral replication cycle by binding to the host protein NCL — a “jack-of-all-trades phosphoprotein” found in the nucleolus.
NCL is a prime hijacking target for the viral nucleoprotein (NP). Like keys to a house, NCL is used by viruses to break in, replicate and exit the nucleus to spread further. By blocking access to what the virus turns into a “viral factory,” the peptide prevents NP trafficking and suppresses viral replication to limit progression of disease.
In influenza A-infected A549 cells, AGM-380d and AGM-380t were found to suppress viral replication by blocking viral NP trafficking. Treatment with either peptide was associated with reduced NP levels in the cytoplasm and simultaneously increased NP levels in the nucleus – a “retention effect” that was confirmed with confocal microscopy. The treated cells showed reduced viral protein synthesis, genome replication and infectious virus titers. The pattern was also observed in influenza B virus (IBV)-infected cells.
The success was owed partially to peptide engineering, which included attaching a 13-amino-acid cell-penetrating peptide, RIMRILRILKLAR, to AGM-330, a previously developed NCL-targeting peptide for cancer diagnosis and drug delivery, to create AGM-380d and AGM-380t.
Unlike AGM-330d alone, which stayed bound to NCL on the cell surface, AGM-380 “remarkably” crossed the plasma membrane, reached the nucleus and mainly colocalized with NCL in the nucleolus, with some presence in the cytoplasm. The delivery workaround helped bypass the problem of low transmembrane efficiency, the researchers said, a common problem for peptides and oligonucleotides.
In safety testing, mice given the maximum dose of AGM-380 at 2 mg/kg/day via intraperitoneal administration showed no clinical toxicity, weight loss or gross abnormalities in major organs. In the lethal challenge model, all vehicle-treated infected mouse controls died within 10 days post-infection, compared with AGM-380d improving survival up to 60% at 2 mg/kg/day and AGM-380t improving survival up to 65% at 1 or 2 mg/kg/day. AGM-380d- or AGM-380t-treated mice also had significantly lower viral protein production, viral genome replication and infectious progeny virus levels in the lungs compared with infected controls. Viral shedding declined progressively post-infection.
In combination with oseltamivir, AGM-380d increased survival to 90%, while AGM-380t plus oseltamivir produced 100% survival. The numbers were compared with AGM-380d (2 mg/kg/day) alone producing 60% survival, AGM-380t alone 65% survival, and oseltamivir alone 40% survival. “Our results show that both AGM-380d and AGM-380t confer robust antiviral activity in vitro and in vivo against diverse IAV and IBV strains, including oseltamivir-resistant isolates,” according to the paper.
Broader antiviral profiling further showed low micromolar activity across seven tested RNA viruses, indicating efficacy against seasonal influenza and pandemic influenza, as well as other RNA virus infections. The broad-spectrum efficacy observed “underscores the fundamental and conserved roles NCL plays across various viral taxa,” the researchers said. “The breadth of activity across multiple strains suggests that these peptides target a fundamental process essential for viral replication that is not readily bypassed by viral mutations.” (Kim, J.-I. et al. PNAS Nexus 2026, Sept 1. doi: 10.1093/pnasnexus/pgag269).

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