Bemnifosbuvir

DOI: 10.1039/d5dd00504c 本文系统梳理人工智能（AI）在天然产物（NPs）抗病毒药物研发全链条的技术应用、核心瓶颈与未来方向，揭示 AI 如何破解病毒快速变异与传统研发滞后的根本矛盾，推动天然产物从经验性筛选向预测性工程化转型。一、研究背景与核心挑战抗病毒研发的时间差困境 病毒缺乏基因组纠错机制，变异速度远超药物研发周期。新冠疫情中，瑞德西韦、帕罗韦德等药物获批时，病毒已完成多代变异，Alpha、Beta、Delta、Omicron 等变异株先后出现，导致药物疗效快速下降。 传统药物研发平均耗时 10-15 年，成本超 20 亿美元，无法应对突发大流行的紧急需求。 天然产物的双重属性 优势：自然界化学多样性最高的来源，60% 以上的抗感染药物源自天然产物；具有多靶点协同作用，不易产生耐药性。代表案例包括青蒿素、甘草酸二铵、阿昔洛韦等。 瓶颈：仅约 1% 的微生物可培养；结构解析耗时费力；药理机制不明确；合成复杂（如长春碱需 30 步酶促反应）。 AI 的变革性潜力 算法进步：Transformer、图神经网络（GNN）将药物 - 靶点相互作用预测精度提升至新高度。 数据基础：ChEMBL 包含超 2030 万条生物活性数据、240 万个独特化合物；TCMSP 收录 29384 种中药成分。 算力支撑：GPU 集群将大模型训练速度提升数个数量级。 图 1呈现 SARS-CoV-2 主要变异株演化与代表性抗病毒药物研发的时间线错位，区分药物重定位（瑞德西韦、伊维菌素）与从头设计（帕罗韦德、AT-527）两条路径，直观展示传统研发模式的结构性滞后。二、AI 在天然产物抗病毒研发中的全流程应用 AI 技术深度整合上游资源挖掘与靶点鉴定、中游药物筛选与优化、下游临床前与临床转化三大阶段，形成端到端智能化研发体系。（一）上游阶段：资源挖掘与靶点鉴定基因组挖掘与生物合成基因簇（BGCs）识别 传统工具 anti-SMASH 依赖规则匹配，对非典型 BGCs 识别率低，假阴性率高。 深度学习模型（如 RNN-based DeepBGC）可识别超出人类定义的序列基序，发现链霉菌等微生物中的新型 BGCs，并建立基因 - 代谢产物关联。 AI 辅助结构解析 三大技术方向：ML/DL 驱动的 MS/MS 谱图注释与子结构预测；LC-MS 保留时间预测与峰特征提取；微晶体电子衍射（MicroED）集成 AI 流水线。 代表性工具：MZmine 3 支持多模态质谱数据整合分析；AI 辅助 MicroED 实现大环天然产物的 3D 结构解析，无需大尺寸单晶。 知识图谱与自然语言处理（NLP） 知识图谱：整合化学结构、生物靶点、生物合成通路、文献引用等多源数据，如 ENPKG 实现植物化合物的质谱 - 基因 - 代谢物关联。 NLP：从古代本草文献与现代医学文献中提取结构化信息，构建 TCMBank 等大型中医药数据库，实现传统经验知识的数字化重构。 AI 驱动靶点鉴定（三位一体框架）化学中心策略 基于配体化学空间，通过迁移学习与矩阵分解预测孤儿配体靶点，如 STarFish、DeepPurpose 平台。 系统中心策略 利用知识图谱与多模态 GNN 分析病毒 - 宿主相互作用网络，发现间接抗病毒靶点。 物理中心策略 基于 AlphaFold 3、RoseTTAFold All-Atom 实现蛋白 - 配体、蛋白 - 核酸相互作用的高精度预测。 图 2 展示 AI 驱动天然产物抗病毒研发的全流程策略，分上游、中游、下游三大模块，可视化各阶段核心技术与应用场景。（二）中游阶段：药物筛选与优化虚拟筛选与先导物发现 QSAR 模型：高数据量下 GNN 与 Transformer 性能最优；低数据量下随机森林等传统模型更具鲁棒性。 结构 - based 筛选：CurvAGN 等曲率自适应 GNN 提升结合亲和力预测精度；Deep Docking 范式通过代理模型排除 99% 以上非结合物，实现万亿级化合物库筛选。 主动学习：将虚拟筛选转化为动态迭代循环，仅需对接不到 1% 的化合物即可发现顶级先导物。 AI 增强药代动力学与毒性（ADMET）预测 多任务学习：同时预测口服生物利用度、血脑屏障穿透性、心脏毒性、CYP 酶抑制、急性毒性等多个端点，实现早期多参数并行优化。 可解释性：SHAP 框架量化分子子结构对 ADMET 性质的贡献，指导定向结构修饰。 工业应用：ADMETLab 3.0 可评估 119 个端点，AUROC 值最高达 0.94；Deep-PK 框架已进入制药企业临床前研究流程。 抗病毒耐药性预测与缓解 主动范式：EVEscape 等模型预测病毒突变轨迹与免疫逃逸机制，提前设计抗变异抑制剂。 耐药性规避：AI 识别耐药特征，通过生成式 AI 建议骨架修饰，绕过常见耐药通路。 生成式 AI 用于新药设计与合成规划 五大主流范式：基于序列的 RNN/Transformer、基于隐空间的 VAE/GAN、基于图的生成模型、扩散模型、进化算法（GA）。 技术特点：扩散模型擅长生成高几何保真度的 3D 分子构象；进化算法可直接嵌入合成可行性约束。 合成规划：与 AiZynthFinder 等逆合成工具联动，生成分子的同时提供可合成路线。 图 3 展示 AI 驱动多任务学习预测天然产物 ADMET 的完整流程，包括数据输入、标准化、GNN 分子嵌入、多任务预测与 SHAP 可解释性分析。 图 4 概述四大类生成式 AI 范式的核心原理与技术优势，包括序列建模、隐空间插值、扩散去噪、进化优化。 （三）下游阶段：临床前与临床应用AI 驱动临床前测试 实验设计优化：贝叶斯优化可减少 40%-50% 的实验量，已应用于青蒿素类似物的体外抗病毒活性测定。 自动化数据分析：CSGO 等深度学习管道实现 H&E 染色组织的全细胞分割，精准量化炎症细胞浸润。 药代动力学外推：ML 增强的生理药代动力学（PBPK）模型将动物到人体的预测误差降低 20%-30%。 核心问题：AI 优先化合物的湿实验验证失败率超 90%，主要源于 PAINS 化合物误判、溶剂化效应忽略与结构可塑性低估。 AI 创新临床试验设计 联邦学习：实现多中心数据的隐私保护协同训练，已用于新冠患者临床结局预测。 NLP 临床数据挖掘：从电子病历中实时提取疗效与不良事件信号。 合成对照臂：GAN 生成合成患者数据，减少安慰剂队列规模，特别适用于罕见病研究。 三、AI 赋能天然产物抗病毒研发的核心瓶颈数据约束 天然产物数据：多模态、异质化、标准化程度低；高质量标注数据稀缺；阴性结果数据严重不足；中医药古籍文本存在歧义与 OCR 错误。 病毒数据：动态变异导致数据分布快速偏移；液 - 液相分离（LLPS）等新型病毒复制机制缺乏结构数据。 模型局限 本质是模式识别，缺乏对化学与生物学机理的深层理解。 难以捕捉天然产物的复杂构象动力学、多靶点协同作用与系统级效应。 对分布外（OOD）病毒变异的泛化能力差，单点突变即可导致预测失效。 合成可及性 直接提取：产量极低（常低于 0.01% 干重）、不可持续、受季节与环境影响。 异源生物合成：存在 “规模化鸿沟”，滴度常停留在 mg/L 级别，难以达到 g/L 的商业化要求。 半合成：受限于试剂可及性与操作成本，难以大规模生产。 四、未来展望与发展方向构建 FAIR 原则的多模态基准数据集 整合天然产物结构、生物合成通路、多维生物活性、ADMET 性质与阴性结果数据。建立标准化评估指标，实现不同模型的公平比较。 模型与算法创新 从相关性预测转向因果推理与机理发现，发展可解释 AI（XAI）与神经符号技术。提升模型对 OOD 数据的泛化能力，开发针对动态靶点与多靶点协同的专用模型。 强化实验闭环与高通量验证 搭建自动驾驶实验室，结合主动学习实现 “设计 - 构建 - 测试 - 学习”（DBTL）闭环。将合成可行性约束提前嵌入分子设计阶段，缩小计算与实验的差距。 跨学科融合与生态构建 推动化学、生物学、医学、数据科学与工程学的深度交叉。建立隐私保护下的全球数据共享机制，打造端到端智能研发生态。 五、研究结论 AI 为天然产物抗病毒研发提供了颠覆性范式，可显著加速资源挖掘、靶点鉴定、筛选优化与临床转化全流程。当前仍面临数据稀缺、模型机理理解不足与合成可及性三大核心瓶颈。通过构建高质量多模态数据集、发展机理驱动的 AI 模型、建立自动化实验闭环与跨学科合作生态，有望将天然产物抗病毒研发从经验性偶然发现转变为预测性工程化设计，实现对快速变异病毒的主动防御，开启人类与病毒博弈的新时代。

BOSTON, May 13, 2026 (GLOBE NEWSWIRE) -- Atea Pharmaceuticals, Inc. (Nasdaq: AVIR) (Atea or Company), a late-stage clinical biopharmaceutical company engaged in the discovery and development of oral antiviral therapeutics for serious viral diseases, today announced that three abstracts have been accepted for presentation at the European Association for the Study of the Liver (EASL) Congress 2026, taking place May 27-30 th in Barcelona, Spain. The presentations include two posters supporting Atea’s fixed-dose combination regimen of bemnifosbuvir, a nucleotide analog polymerase inhibitor, and ruzasvir, an NS5A inhibitor, for the treatment of hepatitis C virus (HCV). Also being presented and designated as a top poster presentation is preclinical data for AT-587, a proprietary oral nucleotide analog recently selected as the Company’s lead clinical candidate for the treatment of hepatitis E virus (HEV). Collectively, these presentations underscore Atea’s continued progress across its antiviral pipeline and highlight Atea’s focus on advancing potential new treatment options for patients with viral hepatitis. “We look forward to sharing new clinical study results at EASL that further support the differentiated target pro the regimen of bemnifosbuvir and ruzasvir for the treatment of HCV,” said Jean-Pierre Sommadossi, PhD, Chief Executive Officer and Founder of Atea. “As we approach topline results from our Phase 3 C-BEYOND and C-FORWARD trials, these data reinforce the regimen’s potential to deliver a best-in-class pro patients living with HCV.” “We’re also excited to highlight new preclinical data for AT-587, our lead clinical candidate for the treatment of HEV, which has earned designation as a top poster presentation,” added Dr. Sommadossi. “With no approved treatment options, HEV remains a significant, under-recognized disease, particularly among immunocompromised patients. We believe AT-587 has the potential to become a first-in-class therapy and look forward to advancing this program into the clinic mid-year as we expand our efforts to address serious viral infections.” The accepted abstracts will be available on the EASL Congress 2026 website following the embargo lift on Wednesday, May 13 th at 8:00 a.m. Central European Time (CET). Poster Presentations at EASL 2026 Congress: Poster ID: TOP-631 Title: Discovery and preclinical pro a first-in-class potent hepatitis E virus inhibitor AT-587 Presenting Author: Qi Huang Date and Time: Thursday, May 28, 8:30 a.m. - 5:00 p.m. CEST Poster ID: FRI-635 Title: Proton-pump inhibitor omeprazole did not affect the plasma pharmacokinetics of bemnifosbuvir and ruzasvir fixed-dose combination in healthy participants Presenting Author: Xiao-Jian Zhou Date and Time: Friday, May 29, 8:30 a.m. - 5:00 p.m. CEST Poster ID: FRI-636 Title: Bemnifosbuvir and ruzasvir administered as a fixed-dose-combination have low potential to inhibit P-gp, BCRP or OATP1B1/3 mediated transport Presenting Author: Xiao-Jian Zhou Date and Time: Friday, May 29, 8:30 a.m. - 5:00 p.m. CEST About Bemnifosbuvir and Ruzasvir for Hepatitis C Virus (HCV) Bemnifosbuvir has been shown in in vitro studies to be approximately 10-fold more active than sofosbuvir (SOF) against a panel of laboratory strains and clinical isolates of HCV GT 1–5. In vitro studies have also demonstrated bemnifosbuvir remained fully active against SOF resistance-associated substitutions (S282T), with up to 58-fold more potency than SOF. The PK pro bemnifosbuvir supports once-daily dosing for the treatment of HCV. Bemnifosbuvir has been shown to have a low risk for drug-drug interactions. Bemnifosbuvir has been administered to over 3,000 subjects and has been well-tolerated at doses up to 550 mg for durations up to 12 weeks in healthy subjects and patients. Ruzasvir has demonstrated highly potent and pan-genotypic antiviral activity in preclinical (picomolar range) and clinical studies. Ruzasvir has been administered to over 2,800 HCV-infected patients at daily doses of up to 180 mg for 12 weeks and has demonstrated a favorable safety profile. The PK pro ruzasvir supports once-daily dosing. About HCV HCV is a blood-borne, single-stranded (ss) RNA virus that primarily infects liver cells. HCV is a leading cause of chronic liver disease and liver transplants, spreading via blood transfusion, hemodialysis and needle sticks, with approximately 240,000 deaths occurring each year. Despite the availability of direct acting antivirals, HCV continues to be a significant global healthcare issue. An estimated 50 million people worldwide are chronically infected with HCV and there are approximately one million new infections each year. In the US, approximately four million people are estimated to have HCV with annual new infections outpacing treatment rates. HCV infections in the US predominate in patients in the age group between 20 and 49 years old, and it is estimated that less than 10% of HCV-infected patients in the US have cirrhosis. Chronic HCV infection is a leading cause of liver cancer in the US, Europe and Japan. About HEV HEV is a ssRNA virus which infects the liver and remains an under-recognized global health challenge with an estimated 20 million acute infections annually. Waterborne transmission of HEV genotypes 1 and 2 causes mostly acute self-limiting hepatitis in developing regions, whereas foodborne transmission of HEV genotype 3 predominates in the US and Europe and is a cause of chronic hepatitis in immunocompromised patients, which can lead to cirrhosis in three to five years. There is a growing number of immunocompromised patients, a population that includes solid organ transplant and hematopoietic stem cell transplant recipients and patients with hematologic malignancies such as multiple myeloma. Each year, in the US and Europe, 3% of the approximately 450,000 patients who have these underlying medical conditions are at risk of developing chronic HEV. There is currently no approved antiviral therapy for HEV, and current off-label treatments have limited efficacy and tolerability, underscoring a clear and urgent unmet medical need. Atea’s initial HEV clinical efforts will focus on developing AT-587 for the treatment of immunocompromised patients with chronic HEV. About Atea Pharmaceuticals Atea is a late-stage clinical biopharmaceutical company focused on discovering, developing and commercializing oral antiviral therapies to address the unmet medical needs of patients with serious viral infections. Leveraging Atea’s deep understanding of antiviral drug development, nucleos(t)ide chemistry, biology, biochemistry and virology, Atea has built a proprietary nucleos(t)ide prodrug platform to develop novel product candidates to treat single-stranded ribonucleic acid, or ssRNA, viruses, which are a prevalent cause of serious viral diseases. Atea plans to continue to build its pipeline of antiviral product candidates by augmenting its nucleos(t)ide platform with other classes of antivirals that may be used in combination with its nucleos(t)ide product candidates. Atea’s Phase 3 program is evaluating the FDC regimen of BEM, a nucleotide analog polymerase inhibitor, and RZR, an NS5A inhibitor, to treat HCV. Atea anticipates initiating clinical development of AT-587, a nucleotide analog, for the treatment of HEV in mid-2026. For more information, please visit . Forward-Looking Statements This press release includes “forward-looking statements” within the meaning of the Private Securities Litigation Reform Act of 1995. Forward-looking statements in this press release include but are not limited to the dates and times of the presentations, statements regarding the potential best-in-class pro the BEM/RZR regimen for the treatment of HCV, the potential to develop a product for the treatment of HEV, anticipated milestone events and timelines for clinical trials including the timeline for readout of the HCV Phase 3 clinical trials results and initiation of the HEV clinical development, future results of operations and business strategy. When used herein, words including “expected,” “should,” “anticipated,” “believe,” “will,” “plans”, and similar expressions are intended to identify forward-looking statements. In addition, any statements or information that refer to expectations, beliefs, plans, projections, objectives, performance or other characterizations of future events or circumstances, including any underlying assumptions, are forward-looking. All forward-looking statements are based upon Atea’s current expectations and various assumptions. Atea believes there is a reasonable basis for its expectations and beliefs, but they are inherently uncertain. Atea may not realize its expectations, and its beliefs may not prove correct. Actual results could differ materially from those described or implied by such forward-looking statements as a result of various important factors, including, without limitation, uncertainties inherent in the drug discovery and development process and the regulatory submission or approval process, unexpected or unfavorable safety or efficacy data or results observed during clinical trials or in data readouts; delays in or disruptions to clinical trials or our business; our reliance on third parties over which we may not always have full control; our ability to manufacture sufficient commercial product; competition from approved treatments for HCV; dependence on the success of Atea’s most advanced product candidates, in particular the BEM/RZR regimen for the treatment of HCV; as well as the other important factors discussed under the caption “Risk Factors” in Atea’s Quarterly Report on Form 10-Q for the quarter ended March 31, 2026 as such factors may be updated from time to time in its other filings with the SEC, which are accessible on the SEC’s website at These and other important factors could cause actual results to differ materially from those indicated by the forward-looking statements made in this press release. Any such forward-looking statements represent management’s estimates as of the date of this press release. While Atea may elect to update such forward-looking statements at some point in the future, except as required by law, it disclaims any obligation to do so, even if subsequent events cause our views to change. These forward-looking statements should not be relied upon as representing Atea’s views as of any date subsequent to the date of this press release. Contacts Jonae Barnes SVP, Investor Relations and Corporate Communications 617-818-2985 barnes.jonae@ateapharma.com Joyce Allaire LifeSci Advisors jallaire@lifesciadvisors.com