Author: Wang, Aoyu ; Wu, Jizhou ; Jiang, Bin ; Wang, Apeng ; Li, Yuhuan ; Lv, Kai ; Liu, Mingliang ; Zhang, Yuehao ; Gao, Rongmei ; Yan, Haiyan ; Zhong, Xijun ; Wu, Wenhao ; Li, Xingqiong

We have already reported the modification on the piperazine and phenyl rings of JNJ4796, a small-molecule fuse inhibitor targeting hemagglutinin (HA). In this study, we described the structure-activity relationship of the benzoxazole and tetrazole rings of JNJ4796. Many derivatives demonstrated good in vitro activity against IAV H1N1and Oseltamivir-resistant IAV H1N1 stains. Although compounds (R)-1e and (R)-1h exhibited excellent in vitro activity, high drug exposure level and low hERG inhibition, they displayed low oral efficacy. Excitedly, (R)-1a, a representative identified in our previous study, was found to show potent in vivo anti-IAV activity with the survival rates of 100%, 100% and 70% at 15, 5 and 1.67 mg/kg, respectively, comparable to JNJ4796. Currently, we are exploring different ways to ease its gastrointestinal response.

01 Oct 2021·European Journal of Medicinal ChemistryQ1 · MEDICINE

Optimization and SAR research at the piperazine and phenyl rings of JNJ4796 as new anti-influenza A virus agents, part 1

Q1 · MEDICINE

Article

Author: Ma, Chao ; Wang, Aoyu ; Zhang, Kai ; Wang, Apeng ; Qin, Xiaoyu ; Gao, Rongmei ; Jiang, Jiandong ; Xu, Shijie ; Liu, Mingliang ; Li, Yuhuan ; Lv, Kai ; Wei, Zengquan ; Yan, Haiyan

JNJ4796, a small molecule fuse inhibitor targeting the conserved stem region of hemagglutinin, effectively neutralized a broad spectrum of group 1 influenza A virus (IAV), and protected mice against lethal and sublethal influenza challenge after oral administration. In this study, we reported the modification and structure-activity relationship (SAR) of C (piperazine ring) and E (phenyl ring) rings of JNJ4796. Compound (R)-2c was identified to show excellent in vitro activity against IAV H1N1 and Oseltamivir-resistant IAV H1N1 stains (IC₅₀: 0.03-0.06 μM), low cytotoxicity (CC₅₀ > 200 μM), accepted oral PK profiles and low inhibition rate of hERG (13.2%, at 10 μM). Evaluation for the in vivo anti-IAV efficacy of (R)-2c will begin soon.

Journal of Biomolecular Structure and Dynamics

Efficiency of membrane fusion inhibitors on different hemagglutinin subtypes: insight from a molecular dynamics simulation perspective

Article

Author: Rajchakom, Chananya ; Rungrotmongkol, Thanyada ; Nunthaboot, Nadtanet ; Nutho, Bodee ; Boonma, Thitiya

The challenge in vaccine development, along with drug resistance issues, has encouraged the search for new anti-influenza drugs targeting different viral proteins. Hemagglutinin (HA) glycoprotein, crucial in the viral replication cycle, has emerged as a promising therapeutic target. CBS1117 and JNJ4796 were reported to exhibit similar potencies against infectious group 1 influenza, which included H1 and H5 HAs; however, their potencies were significantly reduced against group 2 HA. This study aims to explore the molecular binding mechanisms and group specificity of these fusion inhibitors against both group 1 (H5) and group 2 (H3) HA influenza viruses using molecular dynamics simulations. CBS1117 and JNJ4796 exhibit stronger interactions with key residues within the H5 HA binding pocket compared to H3-ligand complexes. Hydrogen bonding and hydrophobic interactions involving residues, such as H38₁, Q40₁, T325₁ (H5-CBS1117), T318₁ (H5-JNJ4796), W21₂, I45₂, V48₂, and V52₂ predominantly contribute to stabilizing H5-ligand systems. In contrast, these interactions are notably weakened in H3-inhibitor complexes. Predicted protein-ligand binding free energies align with experimental data, indicating CBS1117 and JNJ4796's preference for heterosubtypic group 1 HA binding. Understanding the detailed atomistic mechanisms behind the varying potencies of these inhibitors against the two HA groups can significantly contribute to the development and optimization of effective HA fusion inhibitors. To accomplish this, the knowledge of the transition of HA from its pre- to post-fusion states, the molecular size of ligands, and their potential binding regions, could be carefully considered.Communicated by Ramaswamy H. Sarma.

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Indication	Highest Phase	Country/Location	Organization	Date
Influenza A virus infection	Preclinical	CN	Shanghai Qiangsheng Pharmacy Co. Ltd.	07 Mar 2019
Influenza A virus infection	Preclinical	US	Janssen Research & Development LLC	07 Mar 2019

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