HINT1

01月02日的《热心肠日报》，我们解读了 10 篇文献，关注：IBD，免疫细胞，抗体包被菌，代谢免疫，菌群产物，关节炎，免疫耐受，细菌演化，多组学。 ​​ Nature Reviews：IBD中的中性粒细胞（综述） Nature Reviews Gastroenterology and Hepatology——[65.1] ① IBD中的中性粒细胞具有异质性群体和双重功能，对宿主既有害又有保护作用；② 中性粒细胞功能缺陷、肠道菌群改变和肠道炎症之间存在联系，IBD易感基因参与与防御微生物相关的中性粒细胞功能；③ 中性粒细胞影响菌群的组成和功能，尤其是在炎症状态下；④ 肠道菌群调节中性粒细胞的产生和功能，从激活到成熟；⑤ 一些菌群产生的代谢产物已被鉴定为中性粒细胞的活性调节剂；⑥ 阐明中性粒细胞在宿主-菌群互作中发挥的作用，可用于开发IBD新疗法。 【主编评语】 近期研究发现，中性粒细胞在IBD中可能发挥有害及保护的双重作用。Nature Reviews Gastroenterology and Hepatology上发表的一篇综述，讨论了中性粒细胞在IBD中发挥的作用，以及中性粒细胞与肠道菌群的互作。（@aluba） 【原文信息】 Neutrophils: from IBD to the gut microbiota 2023-12-18, doi: 10.1038/s41575-023-00871-3 Nature子刊：转录因子Aiolos如何调控肠上皮内淋巴细胞？ Nature Immunology——[30.5] ① 转录因子Aiolos是Ikzf3编码的Ikaros锌指家族成员之一，Ikzf3−/−CD8αα+型肠上皮淋巴细胞（IELs ）中NK受体、细胞毒性酶、细胞因子和趋化因子表达升高，Aiolos参与抑制IELs的激活；② Aiolos主要作用于CD8αα+IELs中的Tcf7−Il2rbhi亚群，Ikzf3−/−IELs对IL15的反应增强；③ Aiolos与基因的调节区域结合，改变染色质可及性、组蛋白去乙酰化并协调其他转录因子调节IELs效应基因的表达；④ Ikzf3敲除小鼠对结肠炎易感性增加。 【主编评语】 肠上皮内淋巴细胞（IELs）对肠道微环境变化表现出迅速的先天性反应，且被严格控制，但IELs调节机制目前尚未完全明确。近日，发表在Nature Immunology上的这篇文章，揭示转录因子Aiolos抑制肠上皮内淋巴细胞活化机制。（@圆圈儿） 【原文信息】 The transcription factor Aiolos restrains the activation of intestinal intraepithelial lymphocytes 2023-12-04, doi: 10.1038/s41590-023-01693-w 抗体包被逃逸菌是克罗恩病发病潜在机制 Gut——[24.5] ① 与健康对照组相比，严重克罗恩病（CD）患者的肠道细菌IgG2包被水平更高，且活动性CD患者或高的IgA细菌包被会增强IgG2包被的水平；② 高IgG2包被细菌的组成显著不同于低IgG2包被的菌群，其中包含多种CD严重程度表征指标；③ IgG2包被菌同时包括致病菌和非致病菌，流式分析发现IgG2包被菌中仅48%有IgG2包被，还包括大量未包被菌；④ IgG2包被菌总伴随着两种非包被病原体，弯曲杆菌和曼海姆菌，其本身流行性较低，但在CD发作期显著富集。 【主编评语】 克罗恩病（CD）是炎症性肠病中一大类疾病，由于其发病机制复杂，目前尚没有有效的治愈方法，在临床上主要通过监测肠粘膜的动态从而针对性抑制疾病的发作期。从免疫病理学机制来看，CD通常认为是I型和17/3型免疫反应不受控制，尽管已经对引起免疫的细胞因子有了较为清晰的认识，但是对于免疫反应效应因子免疫球蛋白在CD中的作用和特异性目前尚没有相关深入的报道。近期一篇发表在Gut上的研究论文，通过对荷兰30个正常人群队列和60例CD患者，包括发作期和静息期患者中被免疫球蛋白包被菌群的类型进行了详细的研究和分类，发现重度CD患者以及CD活动期与IgG2包被细菌显著相关。同时发现伴随IgG2包被细菌存在的还有两种未包被的病原菌，提示这些逃逸包被的病原菌是CD发作的重要原因。（@Zhonghua） 【原文信息】 Specific gut pathobionts escape antibody coating and are enriched during flares in patients with severe Crohn’s disease 2023-07-02, doi: 10.1136/gutjnl-2023-330677 Nature子刊：IgA缺乏症患者中，IgG和IgM协同包被肠道细菌 Nature Communications——[16.6] ① IgA缺乏的人中，Ig包被整体低3.6倍，但IgM单独以及IgM+IgG包被概括了大多数细菌家族；② 肠道细菌中IgG包被主要以IgG1和IgG4亚型为主，该包被均匀分布于所有受试者，与IgA状态无关；③ 尽管单IgG2涂层在IgA缺乏症的流行率是健康对照组的1.6倍，但它的发病率是炎症性肠病的1/2倍，与粪便中大肠杆菌数量和血液TNF-α水平升高有关；④ 在IgA存在的情况下，IgA单包被细菌居多，而在IgA不存在的情况下，IgM和IgG单包被和双包被细菌居多。 【主编评语】 IgA通过包被微生物，在防御粘膜屏障中发挥作用。但令人惊讶的是，IgA缺乏的人类很少表现出与感染相关的并发症，其中的机制未知。Nature Communications近期发表的文章，发现在缺乏IgA的情况下，IgG有助于IgM包被大多数细菌家族，并将单独IgG2细菌包被鉴定为炎症标志物。（@章台柳） 【原文信息】 IgG and IgM cooperate in coating of intestinal bacteria in IgA deficiency 2023-12-08, doi: 10.1038/s41467-023-44007-2 微生物重塑代谢？代谢自主调节防御病菌！（综述） Trends in Cell Biology——[19] ① 宿主代谢免疫基于细菌生存需求的Goldilocks原则（即不多、不少、正好）自主调节，防御病菌入侵；② 宿主可以限制细菌摄取必须营养元素、能量等抑制其增殖-即“过少”，如中性粒细胞利用二价金属结合蛋白钙卫蛋白扣留病菌所需的金属离子；③ 还可以积累对病菌有害的代谢物杀菌-即“过多”；④ 或同时做到“过少”和“过多”，如巨噬细胞将细菌需要的精氨酸转化为抗菌的一氧化氮衍生物；⑤ 宿主还可以促进共生菌和线粒体代谢，破坏病菌代谢平衡。 【主编评语】 Trends in Cell Biology发表的综述，挑战了病菌感染中宿主仅作为受害者，被重塑代谢的观点。提出宿主可以主动自我调节代谢抵御病菌入侵。（@好雨） 【原文信息】 Metabolic immunity against microbes 2023-11-29, doi: 10.1016/j.tcb.2023.10.013 菌群衍生的吲哚或可刺激关节炎发展？ Journal of Clinical Investigation——[15.9] ① 微生物介导的色氨酸通路在胶原诱导的小鼠关节炎（CIA）模型中改变，其中吲哚水平与疾病严重程度相关，补充吲哚会轻微改变小鼠粪便微生物群多样性和组成；② 补充吲哚会导致IL-6、TNF和IL-1β显著增加，补体激活增加，这是由于同型转换/抗体糖基化模式有利于补体结合；③ 吲哚会导致CIA中Th17的增加，IL-23的中和会降低吲哚诱导的CIA疾病严重程度；④ 将人结肠淋巴细胞暴露于吲哚会增加参与IL-17信号传导和浆细胞激活的基因表达。 【主编评语】 色氨酸分解代谢的改变已在类风湿性关节炎（RA）和脊椎关节炎等炎症性疾病中被发现，但色氨酸代谢物与疾病之间的因果机制尚不清楚。近日，科罗拉多大学安舒茨医学院研究人员在Journal of Clinical Investigation发表最新研究，使用胶原诱导关节炎（CIA）模型，发现色氨酸代谢的改变，特别是吲哚与疾病相关，提示炎症性关节炎期间肠道生态失调导致色氨酸分解代谢改变的机制，从而导致吲哚刺激关节炎的发展，值得关注。（@九卿臣） 【原文信息】 Microbiota-dependent indole production stimulates the development of collagen-induced arthritis in mice 2023-12-19, doi: 10.1172/JCI167671 共生菌通过调节干扰素信号可维持小鼠免疫耐受？ Journal of Experimental Medicine——[15.3] ① 通过共生细菌脆弱拟杆菌利用经典抗病毒途径来调节肠道树突状细胞（DC）和调节性T细胞（Treg）反应；② 共生介导的耐受性需要I型干扰素（IFN）信号传导，IFN受体IFNAR1缺陷的DC在响应脆弱拟杆菌时表现出IL-10和IL-27产生减弱；③ DC中IFN驱动的IL-27对于通过IL-27Rα信号传导形成随后的Foxp3+Treg至关重要；④ 脆弱拟杆菌定植会在肠道炎症期间促进Foxp3+Tregs中独特的IFN基因特征；⑤ 共生介导的免疫耐受通过Tonic I型IFN信号传导发挥关键作用。 【主编评语】 I型干扰素在协调免疫应答中发挥广泛的重要生物效应，已经在病原体清除的背景下进行过经典的研究。然而，免疫调节细菌是否通过IFN途径支持肠道免疫耐受仍然未知。近日，加利福尼亚大学研究人员在Journal of Experimental Medicine发表最新研究，探究共生细菌脆弱拟杆菌利用经典抗病毒途径来调节肠道树突状细胞和调节性T细胞反应，发现共生细菌促进I型干扰素信号传导以维持小鼠的免疫耐受，值得关注。（@九卿臣） 【原文信息】 Commensal bacteria promote type I interferon signaling to maintain immune tolerance in mice 2023-12-12, doi: 10.1084/jem.20230063 肠道炎症期间常驻细菌如何进化并影响临床结果？ Gut Microbes——[12.2] ① 基于IBD无菌小鼠模型探究大肠杆菌体内进化规律，炎症特异性大肠杆菌在模型中明显进化，在所有发炎小鼠中监测到高频率的SNV；② 相比非发炎小鼠分离株，进化改变与发炎环境中更高适应性有关；③ 大规模表型分析发现细菌对炎症的适应会导致临床相关表型，包括对抗生素的附带敏感性；④ 氯化锂存在情况下，野生型小鼠进化细菌种群显示出更高的代谢能力，而在基因敲除小鼠中未观察到这种变化，提示炎症肠道中细菌进化会产生特定遗传和表型特征。 【主编评语】 炎症性肠病是一种影响胃肠道的持续性炎症，在其管理和治疗方面提出重大挑战。尽管我们知道宿主内的细菌进化发生在肠道内，但很少从进化的角度研究这种疾病。近日，基尔大学研究人员在Gut Microbes发表最新研究，基于IBD无菌小鼠模型探究大肠杆菌体内进化规律，发现大肠杆菌在炎症性肠病的小鼠模型中的演变会导致疾病特异性细菌基因型和具有临床相关性的权衡，值得关注。（@九卿臣） 【原文信息】 Evolution of E. coli in a mouse model of inflammatory bowel disease leads to a disease-specific bacterial genotype and trade-offs with clinical relevance 2023-12-07, doi: 10.1080/19490976.2023.2286675 肠道菌群与克罗恩病活动性的异质性关联 Gut Microbes——[12.2] ① 利用分位数回归研究克罗恩病(CD)患者和健康者细菌相对丰度与疾病活动间关系；② 相关性偏离了红蝽菌科、巴氏杆菌科、消化链球菌科、普氏菌科和瘤胃球菌科相对丰度的平均反应；③ 与没有自我报告症状或可测量炎症患者相比，经历恶化的患者的链球菌科相对丰度显著升高；④ 特定细菌家族与CD和恶化有关，但由于病程、用药史、肠道菌群组成等异质性，患者间相关性不同；⑤ CD患者肠道菌群多样性减少，但多样性丧失过程对特定分类群而言是不一致的。 【主编评语】 克罗恩病（CD）与特定的细菌有关联，但研究中报告的关联差异很大。这种不一致性可能是由于个体患者之间的异质性关联，导致与细菌丰度的平均值没有明显或只有微弱的关系。Gut Microbes近期发表的文章，发现特定细菌家族与CD和恶化有关，但由于病程、用药史、肠道菌群组成等异质性，患者间相关性不同。（@章台柳） 【原文信息】 Heterogeneous associations of gut microbiota with Crohn’s disease activity 2023-12-17, doi: 10.1080/19490976.2023.2292239 国内团队：多组学探究IBD发病机制中线粒体功能障碍分子网络 EBioMedicine——[11.1] ① 采用孟德尔随机化和共定位分析，通过多组学探究线粒体相关基因与IBD间关系，鉴定出PARK7和ACADM线粒体基因与IBD和UC有关；② ACADM中基因甲基化与其低表达相关，在PARK7和PDK1中也观察到基因甲基化与其表达间负相关；③ 在循环蛋白水平上，基因预测较高水平的PARK7和HINT1与IBD风险负相关，而较高水平的HINT1和ACADM、PDK1、FIS1分别与CD和UC风险降低相关；④ 线粒体PARK7基因与IBD风险相关，线粒体FIS1、PDK1和ACADM基因与UC风险相关。 【主编评语】 线粒体功能障碍与IBD发展有关，但其遗传病理生理学尚未完全阐明。近日，浙江大学医学院附属第二医院李雪、卡罗林斯卡学院Shuai Yuan、中山大学第一附属医院Shixian Hu及团队在EBioMedicine发表最新研究，采用孟德尔随机化和共定位分析，通过整合多组学来研究线粒体相关基因与IBD之间的关系，鉴定出与IBD相关的线粒体基因，值得关注。（@九卿臣） 【原文信息】 Multi-omic insight into the molecular networks of mitochondrial dysfunction in the pathogenesis of inflammatory bowel disease 2023-12-15, doi: 10.1016/j.ebiom.2023.104934 感谢本期日报的创作者：岳晨博，鹿刺刺，湖人总冠军，Sunflower，Jadon，Zzz，九卿臣 点击阅读过去10天的日报： 01-01 | 12月，最值得看的40篇肠道健康文献！ 2023-12-31 | 26页综述详解：浆果的健康作用和食品价值 2023-12-30 | 多吃还是少吃？10文聚焦食欲调控的奥秘 2023-12-29 | 22页《自然·综述》讲透自闭症与胃肠道的关系 2023-12-28 | 65分综述详解：母亲菌群如何影响孩子免疫发育？ 2023-12-27 | Cell子刊揭秘：肠道衰老，源头在哪？ 2023-12-26 | 《自然·综述》年度回顾：炎症性肠病疗法的新进展 2023-12-25 | 口腔健康莫忽视！12页综述解析牙周炎与癌症的复杂关系 2023-12-24 | 发酵食品如何促进胃肠健康？65分综述一文读懂 2023-12-23 | 肠脑轴前沿：10文一览肠道与脑健康的紧密关系

- Research study demonstrates regulation of chromatin structure and cancer gene expression – - Findings to augment clinical trial in liver cancer - Hepion Pharmaceuticals, Inc. (NASDAQ:HEPA), a clinical stage biopharmaceutical company focused on Artificial Intelligence (“AI”)-driven therapeutic drug development for the treatment of non-alcoholic steatohepatitis (“NASH”), fibrotic diseases, hepatocellular carcinoma (“HCC”), and other chronic diseases, today announced new research findings uncovering a previously unknown mechanism by which Hepion’s lead drug candidate, rencofilstat, may exert anti-cancer activity. The research involved a technique called ATAC-Seq (“assay for transposase-accessible chromatin with sequencing”) that determines what specific DNA sequences are in open or closed states. Gene expression occurs from DNA sites that are in an open state, whereas genes within closed regions are silent. Hepion’s ATAC-Seq experiments on two liver cancer cell lines revealed that rencofilstat significantly changed the open-closed state of DNA. Approximately 4,500 sites were altered within one hour of treatment in both cell lines, which was slightly more than a chemotherapeutic compound, azacytidine, known to alter DNA structure. The predominant effect of rencofilstat – opening or closing – depended on the cell line. Rencofilstat predominantly closed DNA in the cell line in which it also suppressed cell growth, suggesting that the drug candidate’s anti-cancer effect on the cells resulted in part from DNA closure and gene silencing. Another interesting finding was the types of genes that became accessible/inaccessible due to rencofilstat treatment. DNA sites that were opened by rencofilstat were enriched for several well-known tumor suppressor genes such as CDKN1A (p21), PTEN, HINT1, KLF6 and SOCS1; whereas a tumor-promoting oncogene, NOTCH1, was predicted to be silenced by rencofilstat. Accessibility also changed for many genes related to apoptosis, consistent with increasing cancer cell death. Thus, changes in gene accessibility produced by rencofilstat favored an anti-cancer mode of action. Follow-up experiments are planned to further understand the impact on cancer cell growth. “Anti-tumor effects of rencofilstat and other cyclophilin inhibitors observed in many preclinical studies have been attributed to several mechanisms, but changes in DNA accessibility and especially those that potentially limit oncogenesis have never before been reported for this class of drug,” explained Dr. Daren Ure, Hepion’s Chief Scientific Officer. “Knowing now that rencofilstat can modify DNA chromatin structure and regulate what genes are turned on and off gives us new appreciation for the scope of rencofilstat’s actions.” “Rencofilstat previously received Orphan Drug designation for the treatment of NASH. Hepion has also received FDA clearance to begin a Phase 2 clinical trial of rencofilstat in HCC, which remains the most common type of liver cancer, accounting for up to 90% of all primary liver cancers. We believe rencofilstat may be well-positioned to offer a unique approach to treating both NASH and HCC, as these diseases are often intertwined,” commented Hepion’s CEO, Robert Foster. “These newest findings reported today strengthen our resolve to initiate Phase 2 HCC trials pending adequate financial resources. More broadly, rencofilstat’s cumulative properties – liver-targeting, antifibrotic, anti-cancer, antiviral – reinforce Hepion’s focus on two of the most serious liver diseases of the day, NASH and HCC.” About Hepion Pharmaceuticals The Company's lead drug candidate, rencofilstat, is a potent inhibitor of cyclophilins, which are involved in many disease processes. Rencofilstat has been shown to reduce liver fibrosis and hepatocellular carcinoma tumor burden in experimental disease models and is currently in Phase 2 clinical development for the treatment of NASH. In November 2021, the U.S. Food and Drug Administration (“FDA”) granted Fast Track designation for rencofilstat for the treatment of NASH. That was followed in June 2022 by the FDA’s granting of Orphan Drug designation to rencofilstat for the treatment of HCC. Hepion has created a proprietary Artificial Intelligence deep machine learning (“AI/ML”) platform designed to better understand disease processes and identify patients that are rencofilstat responders. This AI/ML has the potential to shorten development timelines and increase the observable differences between placebo and treatment groups. In addition, Hepion’s AI/ML can be used to drive its ongoing NASH and HCC clinical development programs and identify other potential therapeutic indications for cyclophilin inhibition with rencofilstat. The content above comes from the network. if any infringement, please contact us to modify.

Low risk for drug-drug interactions with bemnifosbuvir based upon results from in vitro metabolism and transporter studies Bemnifosbuvir retains activity against all SARS-CoV-2 variants of concern evaluated as well as other human coronaviruses such as HCoV-229E, HCoV-OC43, and SARS-CoV-1 Favorable absorption, distribution, metabolism, and excretion profile demonstrated for bemnifosbuvir Synergistic antiviral effect observed for the combination of bemnifosbuvir and ruzasvir against HCV in vitro BOSTON, March 14, 2023 (GLOBE NEWSWIRE) -- Atea Pharmaceuticals, Inc. (Nasdaq: AVIR) (“Atea”), a clinical-stage biopharmaceutical company engaged in the discovery and development of oral direct acting therapeutics for serious viral diseases, today announced the presentation of new Phase 1, in vitro and in vivo data that demonstrate key profile attributes of Atea’s lead drug candidate, bemnifosbuvir, for the treatment of COVID-19 and hepatitis C (HCV). Additionally, new data for AT-752 for dengue and a nucleotide analogue are being presented. These results are being presented at the 36th International Conference on Antiviral Research (ICAR 2023) taking place March 13-17, 2023 in Lyon, France. Key highlights of the presentations include results from a Phase 1 human absorption, distribution, metabolism, and excretion (ADME) study for bemnifosbuvir demonstrating a favorable ADME profile supportive of the dosing regimen used in SUNRISE-3, a global, multicenter Phase 3 registrational trial for the treatment of COVID-19. In vitro metabolism and transporter interaction studies showed bemnifosbuvir has a low risk for interactions with medicines commonly prescribed to patients at risk for COVID-19 progression and for those with HCV infection. In vitro studies also demonstrated advantages of bemnifosbuvir’s mechanism of action, which targets conserved regions of the viruses that cause COVID-19 and HCV infection. These advantages include a higher barrier to resistance and maintenance of antiviral activity in the presence of COVID-19 variants. Additionally, the combination of bemnifosbuvir and ruzasvir for the treatment of HCV demonstrated potent in vitro synergistic antiviral activity and in vivo preclinical safety without adverse interactions. “As COVID-19 becomes endemic, it is essential to have new oral antiviral medicines that are safe, well tolerated and address the current limitations of existing treatments,” said Bruno Canard, Ph.D., lead investigator of the in vitro studies of bemnifosbuvir conducted at Architecture et Fonction des Macromolécules Biologiques, CNRS and Aix-Marseille University. “The data presented at ICAR demonstrate bemnifosbuvir’s unique metabolic activation pathway and how it inhibits enzymes essential to the viral replication of COVID-19 and HCV and its potential to play an important role in the treatment of these serious viral diseases.” Bemnifosbuvir is an investigational, oral, direct-acting antiviral being evaluated in the Phase 3 SUNRISE-3 trial for the treatment of COVID-19 in non-hospitalized patients at high risk for disease progression, and in Phase 2 development for the treatment of HCV in combination with ruzasvir, an oral NS5A inhibitor. “As we continue to advance late-stage development of bemnifosbuvir, these data demonstrate that our lead compound has the potential to improve the current standard of care and address key unmet needs and limitations for patients with COVID-19 and HCV,” said Jean-Pierre Sommadossi, PhD, Chief Executive Officer and Founder of Atea Pharmaceuticals. “These data support a favorable safety and drug interaction profile of bemnifosbuvir to treat these conditions and to provide vulnerable patients with another therapeutic option.” COVID-19 Oral Presentation Number: 019 Date/Time: Wednesday, March 15 from 10:35 am-10:45 am CET Title: Bemnifosbuvir (BEM, AT-527) a Potent Inhibitor of SARS-CoV-2 Variants of Concern (VOC), and a Promising Oral Antiviral with a High Resistance Barrier for Treatment of COVID-19 and other Coronaviruses Infections In vitro results demonstrate that bemnifosbuvir is a potent inhibitor of all tested SARS-CoV-2 variants of concern as well as other human coronaviruses such as HCoV-229E, HCoV-OC43, and SARS-CoV-1. Results from an in vitro resistance study conducted with the surrogate virus HCoV-229E in Huh7 cells suggest that bemnifosbuvir may have a high barrier to drug resistance during treatment of COVID-19 and other coronavirus infections. Bemnifosbuvir Oral Presentation Number: 047Date/Time: Thursday, March 16 from 5:20-5:30 pm CETTitle: Five Cellular Enzymes in the Activation Pathway of Bemnifosbuvir, a Drug Candidate Against SARS-CoV-2 Infections Results from this in vitro study showed that bemnifosbuvir required a minimal set of 5 cellular enzymes (Cat/CES1, HINT1, ADALP1, GUK1, and NDPK) to be metabolized to its active triphosphate form, AT-9010, with an obligate order of reactions, as demonstrated by functional and structural data at each step. In vitro, AT-9010 inhibits enzymes essential to viral replication such as the SARS-CoV-2 bi-functional nsp12 RNA polymerase/nucleotidyltransferase, the dengue virus bi-functional NS5 RNA polymerase/RNA methyltransferase, and the HCV NS5B RNA polymerase. Poster Number: 537Date/Time: Tuesday, March 14 from 5:00-7:00 pm CET and Wednesday, March 15 from 12:15-2:15 pm CETTitle: Low Risk of Drug-Drug Interactions (DDIs) for Bemnifosbuvir (BEM) Based Upon In Vitro Metabolism and Transporter Interaction Studies Results from these in vitro studies suggest that bemnifosbuvir has a low risk of drug-drug interactions when co-administered with drugs that are substrates of CYP450 enzymes, UGT1A1 or ABC/SLC transporters. The enzymes that support metabolic activation of bemnifosbuvir are of high capacity and are not likely to be inhibited by commonly prescribed drugs. The observations from these in vitro studies have been subsequently validated with Phase 1 clinical drug-drug interaction studies. Poster Number: 549Date/Time: Tuesday, March 14 from 5:00-7:00 pm CET and Wednesday, March 15 from 12:15-2:15 pm CETTitle: Pharmacokinetics and Metabolism of [14C]-Bemnifosbuvir in Healthy Male Participants Results from a Phase 1, open-label, single-dose, mass balance study demonstrated that bemnifosbuvir 550 mg was well absorbed and nearly completely recovered in urine and feces. The data showed bemnifosbuvir and its metabolites did not accumulate in red blood cells, with similar exposure in plasma and whole blood, and that bemnifosbuvir underwent rapid and extensive metabolic activation to the intracellular active triphosphate metabolite and thereafter entered general circulation mostly as nucleoside metabolites. AT-273, the nucleoside metabolite considered a surrogate of the intracellular phosphates, exhibited a long half-life in plasma, supporting once- and twice-daily dosing. Hepatitis C Poster Number: 411Date/Time: Tuesday, March 14 from 5:00-7:00 pm CET and Wednesday, March 15 from 12:15 pm-2:15 pm CETTitle: The Combination of Bemnifosbuvir (BEM) and Ruzasvir (RZR), the HCV NS5B and NS5A Inhibitors, Demonstrates Potent In Vitro Synergistic Antiviral Activity and In Vivo Preclinical Safety Without Adverse Interactions In vitro, the combination of bemnifosbuvir and ruzasvir demonstrated greater inhibition of HCV replication compared to the sum of inhibition of each agent alone in HCV replicon cells, suggesting a synergistic antiviral effect when bemnifosbuvir and ruzasvir are administered together. In a 13-week toxicity study in rats in which bemnifosbuvir and ruzasvir were administered alone or in combination at 500 mg/kg once daily, treatments were well tolerated, and no adverse events were observed. Results demonstrated that systemic exposures of bemnifosbuvir, its metabolites, and ruzasvir were similar when administered independently or in combination, suggesting no significant drug-drug interactions between bemnifosbuvir and ruzasvir. This synergistic activity and no significant drug-drug interactions, together with the previously demonstrated potent, pan-genotypic, antiviral activity of each agent alone, suggest the combination of bemnifosbuvir and ruzasvir has the potential to offer a differentiated, short duration, pan-genotypic, protease inhibitor-sparing regimen for patients with HCV, with or without cirrhosis. Dengue Oral Presentation Number: 046Date/Time: Thursday, March 16 from 4:50-5:00 pm CET Title: AT-752 Targets Multiple Sites and Activities on the Dengue Virus Replication Enzyme NS5 Results from this in vitro study demonstrated the mechanism of action of AT-752. AT-9010, the active triphosphate metabolite of AT-752, inhibited the essential DENV NS5 enzyme. AT-9010 targets two NS5-associated enzyme activities, the RNA 2'-O-MTase and the RNA-dependent RNA polymerase (RdRp) at its RNA elongation step. RNA synthesis inhibition occurred for all 4 DENV serotypes. These results illustrate at atomic resolution (1.97 Å) how RNA cap methylation was prevented by AT-9010. Nucleotide Analogue Poster Number: 504Date/Time: Tuesday, March 14 from 5:00-7:00 pm CET and Wednesday, March 15 from 12:15-2:15 pm CETTitle: A Non-Excisable Nucleotide Analogue Active against SARS-CoV-2AT-1000 is a 2'-ribose modified nucleotide analog, related to bemnifosbuvir but bearing a sulfur atom at its α-phosphate (i.e., α-thio). Results from this in vitro study show that AT-1000 exhibited potent anti-SARS-CoV2 activity, similar to bemnifosbuvir in human airway epithelial cells. Unlike bemnifosbuvir, neither the Sp or Rp isomer binds or inhibits the NiRAN domain nucleotidylation activity. The α-thio modification therefore creates a novel compound, exhibiting an original mechanism of action. These results suggest that this single atom modification may provide a general approach to potentiate a wide array of nucleotide analogues against RNA viruses carrying natural resistance to nucleotide analogue antivirals, such as highly pathogenic coronaviruses. About Bemnifosbuvir for COVID-19 Bemnifosbuvir, a nucleotide polymerase inhibitor, targets the SARS-CoV-2 RNA polymerase (nsp12), a highly conserved gene that is unlikely to change as the virus mutates and new variants continue to emerge. This gene is responsible for both replication and transcription of SARS-CoV-2. Bemnifosbuvir has a unique mechanism of action, with dual targets consisting of chain termination (RdRp) and nucleotityltransferase (NiRAN) inhibition, which has the potential to create a high barrier to resistance. In vitro data confirm that bemnifosbuvir is active with similar efficacy against all variants of concern and variants of interest that have been tested, including Omicron subvariants BA.4 and BA.5. Bemnifosbuvir is currently being evaluated in SUNRISE-3, a global multicenter Phase 3 registrational trial for the treatment of COVID-19. About Bemnifosbuvir and Ruzasvir for Hepatitis C VirusBemnifosbuvir has been shown to be approximately 10-fold more active than sofosbuvir (SOF) in vitro against a panel of laboratory strains and clinical isolates of HCV genotypes 1–5. In vitro studies demonstrated bemnifosbuvir remained fully active against SOF resistance-associated strains (S282T), with up to 58-fold more potency than SOF. The pharmacokinetic (PK) profile of bemnifosbuvir supports once-daily dosing for the treatment of HCV and bemnifosbuvir has been well tolerated at doses up to 550 mg for durations up to 8-12 weeks in healthy and HCV infected subjects. Ruzasvir (RZR), an oral NS5A inhibitor, has demonstrated highly potent and pangenotypic antiviral activity in preclinical (picomolar range) and clinical studies. RZR has been administered to over 1,200 HCV-infected patients at daily doses of up to 180 mg for up to 24 weeks and has demonstrated a favorable safety profile. RZR’s PK profile supports once-daily dosing. The combination of bemnifosbuvir and ruzasvir for the treatment of HCV is in Phase 2 development. About Atea PharmaceuticalsAtea is a clinical stage biopharmaceutical company focused on discovering, developing and commercializing oral therapies to address the unmet medical needs of patients with serious viral infections. Leveraging the Company’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. Currently, Atea is focused on the development of orally-available antiviral agents for serious viral infections, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes COVID-19, and hepatitis C virus (HCV). For more information, please visit www.ateapharma.com. Forward-Looking Statements This press release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. All statements contained in this press release that do not relate to matters of historical fact should be considered forward-looking statements, including without limitation statements regarding our expectations surrounding the potential of our product candidates, including bemnifosbuvir combination product candidates, and expectations regarding our pipeline, including trial design and development timelines. These statements are neither promises nor guarantees, but involve known and unknown risks, uncertainties and other important factors that may cause our actual results, performance or achievements to be materially different from any future results, performance or achievements expressed or implied by the forward-looking statements, including, but not limited to, the uncertainty around and costs associated with the clinical development of bemnifosbuvir as a potential treatment for COVID-19 and the combination of bemnifosbuvir and ruzasvir as a potential treatment for HCV. These and other important factors discussed under the caption “Risk Factors” in our Annual Report on Form 10-K for the year ended December 31, 2022 and our other filings with the SEC 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 we may elect to update such forward-looking statements at some point in the future, we disclaim any obligation to do so, even if subsequent events cause our views to change. Contacts Jonae BarnesSVP, Investor Relations and Corporate Communications617-818-2985barnes.jonae@ateapharma.com Will O’ConnorStern Investor Relations 212-362-1200will.oconnor@sternir.com