Development of 4-(aroylamino)piperidine-based entry inhibitors as anti-influenza therapeutics

开发基于 4-(芳酰氨基)哌啶的进入抑制剂作为抗流感疗法

• 批准号: 10618383
• 负责人: Lijun Rong
• 金额: $ 99.94万
• 依托单位: CHICAGO BIOSOLUTIONS, INC.
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-02 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10618383
• 关键词: Acute; Address; Affinity; Amantadine; Animal Model; Antidotes; Antiviral Agents; Binding; Biochemical; Biological; Biological Assay; Canis familiaris; Characteristics; Chemicals; Clinical Research; Code; Communicable Diseases; Crystallization; Development; Dose; Drug Design; Drug Kinetics; Effectiveness; Epidemic; Evaluation; Exhibits; Family; Future; Genome; Goals; Hemagglutinin; Immunocompromised Host; In Vitro; Infection; Influenza; Influenza A Virus, H5N1 Subtype; Influenza A virus; Influenza Therapeutic; Integration Host Factors; Lead; Libraries; Life Cycle Stages; Maximum Tolerated Dose; Mediating; Methods; Modeling; Morbidity - disease rate; Mus; Mutation; Neuraminidase inhibitor; Oral; Orthomyxoviridae; Oseltamivir; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacology; Pharmacology and Toxicology; Phase; Plasma; Polymerase; Property; Proteins; RNA; Rattus; Recommendation; Research; Resistance; Resolution; Rimantadine; Rodent; Route; Safety; Series; Small Business Technology Transfer Research; Specificity; Structure; Structure-Activity Relationship; Surface; Testing; Therapeutic; Therapeutic Uses; Time; Toxic effect; Toxicokinetics; Toxicology; Treatment Efficacy; Vaccination; Vaccines; Viral; Virulent; Virus; Virus Diseases; Virus Replication; X-Ray Crystallography; analog; anti-influenza; design; drug development; effective therapy; efficacy evaluation; endonuclease; experimental study; genotoxicity; improved; in vivo; in vivo evaluation; influenza M2; influenza infection; influenza virus strain; inhibitor; ion channel blocker; lead optimization; mortality; mouse model; mutant; nanomolar; neutralizing antibody; novel therapeutics; pandemic disease; pandemic influenza; piperidine; pre-clinical; preclinical development; prophylactic; resistant strain; safety study; safety testing; scaffold; seasonal influenza; small molecule; small molecule inhibitor; synergism; targeted treatment; zanamivir

Influenza A viruses belong to the orthomyxoviridae family, and have a negative-sense, segmented RNA genome, which can cause seasonal or pandemic flu with high morbidity and significant mortality. Vaccination is the most prevalent prophylactic means for controlling influenza infections. However, an effective vaccine usually takes at least six months to develop. Furthermore, vaccination has limited effectiveness in the treatment of immunocompromised patients, and its effectiveness is also limited during a pandemic. The current therapeutic options for flu infections are all based on the neuraminidase inhibitors (NAIs; oseltamivir, zanamivir and peramivir), while the influenza M2 ion channel blockers (amantadine and rimantadine) are not now recommended since all of the circulating influenza strains have acquired resistance. (Xofluza, a polymerase acidic endonuclease inhibitor, has just been approved in 2018 and is yet untried during a flu season.) The rapid emergence of the NAI-resistant strains of influenza A viruses strongly suggests that NAIs alone may not be sufficient as effective therapies, and thus new treatment options targeting the other viral/host factors are urgently needed. This application defines a plan to develop potent, small molecule inhibitors, which block entry of influenza A viruses. We have identified compounds that inhibit entry of infectious influenza A viruses, with IC50 values in the nanomolar range. We have synthesized structurally diverse analogs of the anti-influenza hit series using structure-activity relationships (SARs) to improve potency and selectivity; validated the lead inhibitor candidates in the infectious assay and investigated the mechanism of action (MOA) of the these inhibitors; and selected anti-influenza inhibitors with excellent in vitro potency and selectivity values and druglike in vivo pharmacokinetic properties. In this Fast Track STTR Phase I &II application, we propose four specific aims: (1) optimize the lead scaffold and select development candidates; (2) investigate the mechanism of action (MOA) of the advanced lead compounds with HA proteins; (3) evaluate the pharmacokinetics/toxicokinetics of the advanced lead compounds; and (4) preclinical development.

甲型流感病毒属于正黏液病毒科，具有负义的分段RNA