A PHASE 1, OPEN-LABEL, RANDOMIZED, SINGLE DOSE, CROSSOVER STUDY TO DETERMINE THE BE OF NIRMATRELVIR FOLLOWING ORAL ADMINISTRATION OF FDC TABLETS RELATIVE TO THE PAXLOVID® COMMERCIAL TABLETS IN HEALTHY ADULT PARTICIPANTS UNDER FASTED CONDITIONS

Medicines that may have different names or be made in different ways but have the same effect on the body are called bioequivalent.
The purpose of this study is to learn about the bioequivalence of nirmatrelvir plus ritonavir after taking 2 different combination tablet forms by mouth. These combination tablets are compared to the tablet formulation that is already in the market. This study will be done under fasted conditions in healthy adult participants.
This study is seeking participants who are:
Male and non-pregnant female participants aged 18 years and above.
with a body weight of more than 50 kilograms and Body Mass Index (BMI) between 16 to 32 kilograms per meter squared.
are healthy as confirmed by medical history, physical examination, laboratory tests.
The study will also look at the safety and tolerability of nirmatrelvir plus ritonavir combination tablet and marketed tablet formulations in healthy adult participants.
The study will consist of 4 treatments:
Treatment A: Single oral dose of nirmatrelvir plus ritonavir 150 (1 × 150)/100 milligrams marketed tablets under fasted conditions (Reference 1) Treatment B (low dose strength): Single oral dose of nirmatrelvir plus ritonavir 150/100 milligrams (2 × [75/50 milligrams]) combination tablets under fasted conditions (Test 1) Treatment C: Single oral dose of nirmatrelvir/ritonavir 300 (2 × 150)/100 milligrams marketed tablets under fasted conditions (Reference 2) Treatment D (high dose strength): Single oral dose of nirmatrelvir/ritonavir 300/100 milligrams (2 × [150/50 milligrams]) combination tablets under fasted conditions (Test 2)
All treatments will be given under fasted conditions. Fasted condition means the participants would not have had anything to eat before taking the medicines.
Around 28 participants will be enrolled in the study. Healthy participants will be tested to see if they can be in the study within 28 days before receiving the study medicine. Selected participants will be admitted to the clinical research unit (CRU) one day before receiving the study medicine and will remain in the CRU until discharge after completing all the treatment periods.
On Day 1 of each period, participants will be given a single dose of study medicine nirmatrelvir/ritonavir 300/100 mg or 150/100 mg by mouth by chance. Study medicine will be given with approximately 240 milliliters of room temperature water under fasted conditions (overnight fast of at least 10 hours and no food until 4 hours after receiving the study medicine). Blood samples will be collected at different times of the day up to 48 hours after taking the study medicine. Participants will be discharged from the CRU on Day 3 of Period 4, after all the study related procedures have been completed.
A follow-up call will be made to participants around 28 to 35 days from receiving the final dose of the study medicine. The study will look at the experiences of participants receiving the study medicine. This will help to understand if the study medicine is safe and effective.

开始日期2025-02-14

申办/合作机构

Pfizer Inc.

NCT06078202 / Withdrawn临床1期

Assessment of the Relative Bioavailability of Three Immediate-Release Tablet Formulations of ABBV-903 in Healthy Volunteers

The purpose of this study is to evaluate the relative bioavailability of three immediate-release table formulations of ABBV-903 under fasting conditions in healthy volunteers, and to evaluate the effect of food on the pharmacokinetics of three immediate-release table formulations of ABBV-903.

开始日期2024-12-01

申办/合作机构

AbbVie, Inc.

NCT06646042 / Not yet recruiting临床1期

A PHASE 1, OPEN-LABEL, FIXED SEQUENCE STUDY TO ESTIMATE THE EFFECT OF CARBAMAZEPINE ON THE PHARMACOKINETICS OF IBUZATRELVIR IN HEALTHY ADULT PARTICIPANTS

The purpose of this study is to estimate the effect of carbamazepine, a strong CYP3A4 inducer, on the pharmacokinetics (PK) of ibuzatrelvir in healthy participants.
This study is seeking participants who:
* are male or female that are not of childbearing potential of 18 years of age or older
* are examined to be healthy
The study will consist of two treatments: (1) a single oral dose of ibuzatrelvir 600 mg alone in Period 1 and (2) carbamazepine q12h (BID) titrated from 100 mg to 300 mg over 15 days with a single ibuzatrelvir 600 mg dose coadministered on day 15 in Period 2. All treatments will be taken by mouth.
All participants will remain in the study clinic for 18 days for safety review, laboratory collections, and to collect samples for PK.
All participants selected in the study will be required to go through a screening period up to 28 days. A screening period is the time during which a few participants are examined to see whether they are fit for the study. During this period, the participant's medical history and past and current medications will be reviewed. A series of tests will also be performed to see if they are good to be selected for the study. If the participant meets all required criteria and are interested in continuing, the participant will be brought into the study clinic to stay overnight for 18 days. About 28 to 35 days after discharge following the final treatment, the participant will be contacted for a follow up visit either in person or by telephone. This is to check up on how the participant is doing and to conclude the study.

开始日期2024-11-06

申办/合作机构

Pfizer Inc.

100 项与 SARS-CoV-2 3CLpro 相关的临床结果

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100 项与 SARS-CoV-2 3CLpro 相关的转化医学

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0 项与 SARS-CoV-2 3CLpro 相关的专利（医药）

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721

项与 SARS-CoV-2 3CLpro 相关的文献（医药）

2024-12-01·Journal of Molecular Graphics and Modelling

Evaluation of inhibition effect and interaction mechanism of antiviral drugs on main protease of novel coronavirus: Molecular docking and molecular dynamics studies

Article

作者: Gao, Sendan ; Zhang, Shouchao ; Wang, Cuihong ; Liu, Lijuan ; Gao, Xin ; Jiang, Yue ; Zhang, Meiling

The outbreak of pneumonia caused by the novel coronavirus (SARS-CoV-2) has presented a challenge to public health. The identification and development of effective antiviral drugs is essential. The main protease (3CLpro) plays an important role in the viral replication of SARS-CoV-2 and is considered to be an effective therapeutic target. In this study, according to the principle of drug repurposing, a variety of antiviral drugs commonly used were studied by molecular docking and molecular dynamics (MD) simulations to obtain potential inhibitors of main proteases. 24 antiviral drugs were docked with 5 potential action sites of 3CLpro, and the drugs with high binding strength were further simulated by MD and the molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) binding free energy calculations. The results showed that the drugs with high flexibility could bind to 3CLpro better than those with low flexibility. The interaction mechanism between antiviral drugs and main protease was analyzed in detail by calculating the root mean square displacement (RMSD), root mean square fluctuation (RMSF) and interaction residues properties. The results showed that the six drugs with high flexibility (Remdesivir, Simnotrelvir, Sofosbuvir, Ledipasvir, Indinavir and Raltegravir) had strong binding strength with 3CLpro, and the last four antiviral drugs can be used as potential candidates for main protease inhibitors.

2024-11-01·Bioorganic & Medicinal Chemistry Letters

Discovery of the potent covalent inhibitor with an acrylate warhead for SARS-CoV-2 3CL protease

Article

作者: Cheng, Yan ; Zhou, Liping ; Shen, Wen ; Shen, Jingshan ; Zhang, Yan ; Jiang, Xiangrui ; Sun, Haiguo ; Chen, Xinyao

COVID-19 has caused severe consequences in terms of public health and economy worldwide since its outbreak in December 2019. SARS-CoV-2 3C-like protease (3CL^pro), crucial for the viral replications, is an attractive target for the development of antiviral drugs. In this study, several kinds of Michael acceptor warheads were utilized to hunt for potent covalent inhibitors against 3CL^pro. Meanwhile, novel 3CL^pro inhibitors with the P3-3,5-dichloro-4-(2-(dimethylamino)ethoxy)phenyl moiety were designed and synthesized which may form salt bridge with residue Glu166. Among them, two compounds 12b and 12c exhibited high inhibitory activities against SARS-CoV-2 3CL^pro. Further investigations suggested that 12b with an acrylate warhead displayed potent activity against HCoV-OC43 (EC₅₀ = 97 nM) and SARS-CoV-2 replicon (EC₅₀ = 45 nM) and low cytotoxicity (CC₅₀ > 10 μM) in Huh7 cells. Taken together, this study devised two series of 3CL^pro inhibitors and provided the potent SARS-CoV-2 3CL^pro inhibitor (12b) which may be used for treating coronavirus infections.

2024-11-01·Bioorganic & Medicinal Chemistry

Structure-guided design and photochemical synthesis of new carbamo(dithioperoxo)thioates with improved potencies to SARS-CoV-2 3CLpro

Article

作者: Yin, De-Hang ; Tian, Jun ; Meng, Jin-Xi ; Gao, Wen-Chao ; Li, Zi-Ying ; Li, Jia ; Gao, Hang ; Chen, Shizhao ; Zhao, Cheng ; Li, Shuai-Shuai ; Yin, Bing-Qian ; Xin, Jie ; Lin, Yue-Chi

The COVID-19 pandemic, caused by the SARS-CoV-2 virus, has triggered a protracted global pandemic from 2019 to 2022, and posed a significant threat to human health. One of the non-structural proteins 3CL^pro of SARS-CoV-2 is considered as a validated target for the development of inhibitors against the virus. Disulfiram has been reported as a covalent inhibitor of 3CL^pro; however, its structure lacks bonding site with active pockets of 3CL^pro and its highly symmetric structure doesn't match well with the irregular cavity of the active center, limiting its therapeutic applications. To enhance their affinity for the 3CL^pro target, in this study, two kinds of disulfiram derivatives, designed based on the reevaluation and optimization of disulfiram, have been synthesized through photoredox chemistry, and the novel carbamo(dithioperoxo)thioates 4g-m were found to display 5-17 folds potency against SARS-CoV-2 3CL^pro compared to the parent disulfiram, with resulting half-maximal inhibitory concentration (IC₅₀) values ranging from 0.14-0.47 μM. Carbamo(dithioperoxo)thioates 4i containing a 4-hydroxy piperidine and a 4-trifluoromethyl phenyl ring, was identified as the most potent inhibitor to both 3CL^pro (IC₅₀ = 0.14 μM) and PL^pro (IC₅₀ = 0.04 μM). Furthermore, molecular dynamics simulations, binding free energy analysis and mass analysis were performed and provided insights on the stability, conformational behavior, and interactions of 4g with 3CL^pro. The green synthetic methodology, the privileged carbamo(dithioperoxo)thioate scaffold, and the molecular mechanisms presented might serve as a useful system for the further discovery of highly potent inhibitors targeting SARS-CoV-2 3CL^pro.

293

项与 SARS-CoV-2 3CLpro 相关的新闻（医药）

2024-09-28

·GlobeNewswire-Health Care

Cocrystal Pharma Advances Oral Pan-Viral Protease Inhibitor CDI-988 into Phase 1 Multiple-Ascending Dose Cohorts

Sept. 26, 2024 -- Cocrystal Pharma, Inc. (Nasdaq: COCP) (“Cocrystal” or the “Company”) announces dosing of the first subjects in the multiple-ascending dose (MAD) portion of the Phase 1 study with CDI-988, its potent, broad-spectrum, oral pan-viral protease inhibitor. Topline study results are expected in late 2024 or early 2025. CDI-988 was specifically designed and developed using Cocrystal’s proprietary structure-based drug discovery platform technology and is being developed as the first-in-class pan-viral antiviral for the treatment of viral gastroenteritis and COVID-19 caused by noroviruses and coronaviruses, respectively. “We are delighted to advance the clinical evaluation of CDI-988, a novel direct-acting antiviral (DAA) targeting the viral proteases of noroviruses and coronaviruses,” said Sam Lee, Ph.D., Cocrystal’s President and co-CEO. “Multiple-ascending dose results will further evaluate safety and tolerability of this potentially groundbreaking antiviral therapeutic.” This randomized, double-blind Phase 1 study, which is being conducted at a single center in Australia, is evaluating the safety, tolerability and pharmacokinetics of orally administered CDI-988 compared with placebo in healthy adults. In July 2024 Cocrystal reported favorable safety and tolerability results from study participants in the single-ascending dose (SAD) portion of the trial. All SAD participants completed the study with no reported serious adverse events or severe treatment-emergent adverse events. No clinically significant observations were noted in laboratory assessments, physical exams or electrocardiograms. Human noroviruses are highly contagious, constantly evolving, extremely stable in the environment and associated with debilitating illness. Symptoms include vomiting and diarrhea, with or without nausea and abdominal cramps. Norovirus infection can be much more severe and prolonged in specific risk groups including infants, children, the elderly and people with immunodeficiency. In the U.S. alone, noroviruses are responsible for an estimated 21 million cases of acute gastroenteritis annually, including 109,000 hospitalizations, 465,000 emergency department visits and nearly 900 deaths, according to the Centers for Disease Control and Prevention (CDC). The estimated annual burden of noroviruses to the U.S. at $10.6 billion, according to the National Institutes of Health (NIH). Outbreaks occur most commonly in semi-closed communities such as nursing homes, hospitals, cruise ships, schools, disaster relief sites and military settings. To date, no antiviral treatment or vaccine is approved for norovirus infections. Coronaviruses (CoV) are a family of viruses that historically have been associated with a wide range of symptoms, ranging from no symptoms at all to more severe disease that includes pneumonia, acute respiratory distress syndrome (ARDS), kidney failure and death. By targeting the viral replication enzymes and protease, Cocrystal believes it is possible to develop an effective treatment for all coronaviruses, including SARS-CoV-2 (which causes COVID-19) and its variants, ARDS and Middle East Respiratory Syndrome (MERS). The ability of an asymptomatic individual to transmit infection heightened the public health challenge of COVID-19. Cocrystal Pharma, Inc. is a clinical-stage biotechnology company discovering and developing novel antiviral therapeutics that target the replication process of influenza viruses, coronaviruses (including SARS-CoV-2), noroviruses, and hepatitis C viruses. Cocrystal employs unique structure-based technologies and Nobel Prize-winning expertise to create first- and best-in-class antiviral drugs. For further information about Cocrystal, please visit www.cocrystalpharma.com. The content above comes from the network. if any infringement, please contact us to modify.

临床结果

2024-09-20

·药通社

首次落地北方！第九届京津冀生物医药创新者峰会报名开启

近百年以来，小分子药物一直是制药行业的支柱。随着抗体、基因疗法、细胞疗法等新兴药物模式的兴起，小分子药物一度被认为即将过时，然而小分子药物事实上仍有其不可替代性。在过去的15 到 20年里，大量小分子药物获得FDA批准，并深刻影响了患者护理，包括用于治疗抑郁和焦虑的度洛西汀（Cymbalta），用于治疗勃起功能障碍的西地那非（Viagra），治疗NSCLC的靶向药奥希替尼（Tagrisso）以及用于心房颤动和抗凝的阿哌沙班（Eliquis）。去年FDA批准的新型小分子药物增加了50%以上，2023年有34个小分子创新药获批，而2022 年仅为21个。此外，小分子药物也占到了2023年FDA批准新药总数的62%，这表明小分子仍然对医疗保健的进步至关重要。小分子过去是、现在是、未来也将是临床治疗药物的主力！ 11月27-28日药融圈将在北京举办第九届生物医药创新者峰会，本次会议以“创新驱动，国际合作”为主旋律，针对小分子领域，包括小分子创新药项目展示，小分子cmc，新技术&新趋势。基本信息会议时间：2024年11月27-28日会议地点：北京会议规模：1000人主办单位：药融圈扫描下方二维码报名大会亮点行业领袖汇聚：会议将邀请生物医药行业领袖、专家学者和企业家，为参会者提供与行业顶尖人士交流的宝贵机会丰富话题设计：会议将围绕小分子药物的最新研究进展、cmc等前沿话题专业论坛交流：设有6个专业论坛，包括新药行业前沿趋势、未满足的临床需求、ADC新药开发，小分子cmc等商务合作机会：会议提供赞助、参展、演讲等多种商务合作形式，为企业提供品牌宣传和合作交流的机会论坛框架专题1：新药行业前沿趋势及投融资专题2：未满足的临床需求专题3：ADC新药开发创新论坛专题4：小分子cmc开发专题5：以临床转化为导向的临床前评价技术与经验分享拟定话题 DAY1 论坛1：新药行业前沿趋势及投融资全球不同疾病领域的市场情况和发展趋势全球热门靶点新药市场竞争格局和发展趋势 NewCo模式为本土药企出海带来了哪些机会？未来医美市场前景和机会未来减重市场的前景和机会未来核药的市场前景和机会未满足临床需求以STING激活剂为载荷的iADC-肿瘤免疫治疗新机遇选择性EGFR-PROTAC药物HJ-002治疗非小细胞肺癌的开发和展望调控人体异常免疫反应的创新药物研发抗感染新药管线布局及研发趋势基于GLP-1的多重受体激动剂治疗肥胖和NASH研究进展小分子眼科药物的突破和临床转化 CNS药物开发的挑战与新机遇针对炎症和癌症的共同机理开发新型创新药物 DAY1 论坛2：ADC新药开发论坛 ADC药物linker的优化 ADC payload该如何筛选？ ADC+IO有望拓展尿路上皮癌早线适应症通过定点整合细胞株加速创新型ADC分子开发的策略基于可开发性与可生产性ADC定点偶联技术研发 ADC药物制剂产品开发的关键考量偶联药物的剂型及制剂处方筛选考量 ADC药物理想的DAR值控制策略高毒素Payload的偶联策略 PROTAC+ADC＝DAC(定向降解抗体偶联物)的作用机制 ADC药物中美IND，CTA，BLA“/NDA,MAA申报策略及难点分析 ADC药物生产及稳定性评估 ADC药物的工艺放大与商业化生产策略双/多特异性抗体结构的多样性带来的生产上的挑战 DAY2 论坛1：小分子cmc开发 API开发中不同阶段工艺开发策略创新原料药不同研发阶段的质量控制标准原料药工艺变更后的杂质研究 CMC申报中原料药常见的问题有哪些? 小核酸药物的药学研究多肽药物的工艺与质量控制创新药CMC研究难点分析和注册策略探讨创新药质量研究方法及策略化学创新药不同研发阶段的质量研究难溶性药物制剂开发策略创新药药学研究的法规考虑创新药CMC中美双报质量研究要求 DAY2 论坛2：以临床转化为导向的临床前评价技术与经验分享自身免疫相关适应症非临床安全性评价代谢疾病热门靶点与临床前药效评价方法人源化小鼠模型在药物毒理研究中的应用心血管系统疾病药物开发的动物模型选择肿瘤治疗性疫苗非临床安全性评价策略帕金森药物的研发现状及临床前研究案例未满足临床需求抗肿瘤小分子激酶抑制剂的研发高选择性BTK-PROTAC和GSPT1分子胶降解剂研发实例新冠3CL蛋白酶抑制剂FB2001研发进展针对难成药性靶点的小分子药物研究 GnRH拮抗剂小分子创新药实例分享往届嘉宾商务合作赞助/参展/演讲火热招募中！主题演讲、展位产品展示、广告赞助、独家会议袋/吊绳/吊牌等多种合作形式开放，为您提供全方位品牌宣传及合作交流平台，诚邀您的参与！商务合作福利、收费标准等详情请咨询：周女士 15858667450 李先生 13340291890 高女士 13191573661 刘女士 18721359843 政府合作咨询：孙先生 18800108389 *报名通道限时免费参会咨询：林女士 18857750934 往届精彩

抗体药物偶联物细胞疗法引进/卖出

2024-08-09

·CPHI制药在线

天然药物抗呼吸道病毒感染作用机制研究进展

关注并星标CPHI制药在线呼吸道病毒是以呼吸道为侵入门户，在呼吸道黏膜上皮细胞中增殖，引起呼吸道局部感染或呼吸道以外组织器官病变的一类病毒，主要包括正黏病毒科（流感病毒）、副黏病毒科（副流感病毒、呼吸道合胞病毒、麻疹病毒、腮腺炎病毒、亨德拉病毒、尼帕病毒、人偏肺病毒）、冠状病毒科（SARS-CoV、MERS-CoV、2019-nCoV冠状病毒）、披膜病毒科（风疹病毒）、小RNA病毒科（鼻病毒）等不同病毒科的多种病毒。呼吸道病毒感染是全球范围内人类发病和死亡的主要原因之一，多数急性呼吸道感染是由病毒引起的。天然药物主要通过直接和间接途径发挥抗呼吸道病毒感染类疾病，直接作用是指抑制病毒的吸附和阻止病毒释放，从而保护机体细胞不受损害，间接作用则是通过免疫调节作用起到抗病毒效果。 1、抑制病毒的吸附和阻止病毒释放血管紧张素转化酶2 (angio‐tensin-converting enzyme 2，ACE2) 是存在于宿主细胞上的一种受体，新型冠状病毒表面的刺突蛋白可以协助病毒找到宿主细胞上的 ACE2 受体并诱导病毒与受体细胞相结合，吸附宿主细胞，在酶的反应下病毒的包膜与宿主细胞融合进而入侵宿主细胞。研究发现青蒿素及其衍生物可以缠绕新冠病毒刺突蛋白的Lys353和Lys31 结合位点，从而影响其与人体ACE2受体蛋白的融合，从而阻止病毒吸附宿主细胞。高分辨质谱和ACE2生物色谱法筛选确定连花清瘟中的大黄酸、连翘苷A、连翘苷I、新绿原酸及其异构体对ACE2具有高度抑制作用。姜黄素、醉茄素A、胡椒碱、芒果苷、蒂巴因、小檗碱、穿心莲内酯和印楝素对SARS-CoV-2 的刺突蛋白和ACE2 受体均具有显著的结合亲和力，可以阻断刺突蛋白与ACE2 受体的结合从而抑制病毒吸附宿主细胞。中药丹参水溶性单体成分丹酚酸可通过阻止刺突蛋白六螺旋束结构形成，有效抑制新型冠状病毒的吸附。血凝素（HA）和神经氨酸酶（NA）是流感病毒包膜上的2种糖蛋白，在流感病毒入侵宿主细胞及传播的过程中扮演着重要的角色。HA可识别并结合宿主细胞表面的唾液酸受体，使病毒粘附于宿主细胞表面、介导病毒包膜与胞内体膜融合；NA能够水解宿主细胞表面的唾液酸释放新病毒。研究发现，槲皮素可通过与流感病毒血凝素蛋白结合，竞争性抑制流感病毒血凝素与宿主细胞的唾液酸结合，抑制病毒包膜与宿主细胞膜融合，抑制病毒以胞吞形式入侵宿主细胞。发酵人参提取物可通过抑制HA、NA活性对H1N1、H3N2、H5N1、H7N9病毒起到治疗作用。穿心莲内酯磺化物可通过抑制HA活性实现抗H1N1、H3N2、乙型流感病毒（IBV）的作用。大蒜素可以用作H1N1的NA、HA、M2蛋白通道的有效多靶点抑制剂，黄芩苷可通过抑制病毒的血凝素HA2亚基活性而抑制H5N1禽流感病毒的进入。安石榴苷能抑制流感病毒的神经氨酸酶，阻止唾液酸的分解，阻断病毒释放。诃子酸和诃子林鞣酸可以抑制病毒NA蛋白的活性，破坏病毒与宿主细胞上唾液酸的结合，在感染的细胞中阻止病毒释放。人呼吸道合胞病毒 (human respiratory syncytial virus，HRSV) 含有三种膜结合蛋白：附着蛋白(G)、融合蛋白(F)、病毒孔蛋白 (SH)。蛋白G可与宿主细胞结合，蛋白F可以融合病毒和细胞膜，使病毒核糖核蛋白能够到达细胞质。三种糖蛋白相互作用使病毒入侵宿主细胞。甘草可通过抑制病毒附着、内化减少HRSV感染，18β-甘草次酸是影响甘草抗HRSV 活性的活性成分之一。穿心莲内酯衍生物可有效抑制HRSV包膜表面糖基蛋白荧光肽的裂解，阻止病毒入侵细胞。车前草醇提液可通过与HRSV竞争结合Hep-2细胞表面的特异性受体抑制HRSV的吸附过程，同时可直接杀死病毒，发挥抗RSV作用。 2、抑制病毒的增殖病毒感染特定的活细胞后，可以在病毒核酸的控制下，利用宿主细胞的能量系统、核糖体等合成病毒核酸和蛋白质，最后组装成结构完整、具有感染力的成熟病毒颗粒。冠状病毒3C 样蛋白酶(3C-like protease，3CLpro) 与木瓜蛋白酶样蛋白酶(papain-like protease，PLpro) 在病毒增殖过程能够将多肽链切割分解成病毒复制需要的片段。通过研究发现，木犀草素、β-谷甾醇、芒柄花黄素、紫檀素、蒙花苷、金丝桃苷等通过与3CLpro特异性结合，阻止3CLpro发挥作用。萝卜硫素 (SFN) 是一种缓慢结合的抑制剂，SFN与3CLpro能够发生共价反应，形成了SFN-3CLpro复合物，从而阻断3CLpro的作用。杨梅素可以与3CLpro共价结合，阻止3CLpro发挥作用，从而抑制病毒的增殖。冬凌草甲素不仅能够抑制3CLpro 的活性，而且在高浓度下可以阻止PLpro主导的反应活动，从而阻止病毒的增殖。新橙皮苷、蛇床子素等与PLpro结合，阻止PLpro发挥作用，从而抑制病毒增殖。西北甘草异黄酮和甘草异黄酮 A可以与RNA依赖的RNA聚合酶 (RNA-dependent RNA polymerase，RdRp) 结合形成复合物，阻止RdRp发挥作用，从而抑制病毒的增殖。核因子-κB (nuclear factor-κB，NF-κB) 信号通路可以调节流感病毒RNA合成，在病毒的复制过程中发挥重要作用。葡萄红素B能够抑制H1N1病毒在MDCK和A549细胞中的复制，并通过IκB激酶 (IκB kinase，IKK) 去磷酸化抑制NF-κB 转入细胞核，从而降低了病毒诱导的活性氧 (reactive oxygen species，ROS)的生成。细胞周期蛋白依赖性激酶抑制剂p21可以直接与病毒聚合酶酸性蛋白结合，并通过破坏核糖核蛋白复合物的形成来限制IAV聚合酶活性，从而阻止病毒增殖。免疫调节病毒感染机体时，巨噬细胞是防御系统的第一道屏障，产生各种抗病毒因子如白细胞介素IL-1、IL-6、肿瘤坏死因子TNF⁃α等，介导机体发挥抗病毒免疫应答，进而抑制和清除体内病毒细胞。人参多糖治疗H9N2感染的鸡发现，其胚胎成纤维细胞CEF中MHC Ⅱ基因表达及细胞因子IL-2、IL-4、IL-10水平升高，表明人参多糖可通过增强体液免疫应答促进机体抗病毒活性。儿茶提取物可增强流感病毒感染小鼠的细胞免疫，还能促进特异性中和抗体产生。干扰素是细胞相互交流以预防和根除病毒感染的一种手段，分为Ⅰ型、Ⅱ型、Ⅲ型。先天性免疫细胞分泌的以IFN⁃α 与IFN⁃β 为主的Ⅰ型干扰素（IFN）介导的天然免疫机制是宿主细胞抵抗冠状病毒最重要的方式之一。研究报道，黄檗水提物通过诱导Ⅰ型干扰素（IFN⁃β）或促炎性细胞因子（IL-6、TNF⁃α）和随后刺激在宿主细胞中的抗病毒状态，从而抑制病毒复制，提高小鼠对甲型流感病毒H1N1、H5N2、H7N3、H9N2的感染存活率。IFN⁃γ 属于Ⅲ型干扰素，主要由Ⅰ型辅助性T细胞（Th1细胞）及自然杀伤细胞产生。研究表明，红参水提物可通过抑制HRSV诱导的小鼠树突状和巨噬细胞样细胞中炎性因子TNF⁃α、IL-6、IL-8表达和人肺上皮细培养液中活性氧的形成，降低肺病毒载量，增强干扰素IFN⁃γ分泌以及增加小鼠 HRSV感染后CD8+T细胞和CD11c+树突状细胞的数量等多种机制发挥抗HRSV作用。此外，红参水提取物可诱导甲型流感病毒H5N1感染的小鼠肺组织IFN⁃α、IFN⁃γ 产生，增强免疫从而减轻H5N1流感病毒的感染。视黄酸诱导基因1样受体（RLRs）信号通路在抗病毒免疫的过程中发挥着重要作用。当16HBE细胞被H1N1 病毒感染后，炎症因子IL-4、IFN⁃γ、RLRs通路相关因子RIG-Ⅰ、IFN⁃β 启动子刺激物⁃1（IPS-1）、IRF-7、IRF-3、NF⁃κB水平均升高，穿心莲内酯干预后上述因子水平均降低，提示穿心莲内酯可通过降低其信号因子来影响RLRs信号通路。研究发现，连翘酯苷A可通过降低小鼠肺部免疫细胞的RLRs信号通路相关蛋白RIG-Ⅰ、MAVS、NF?κBp65表达，降低Th 1/Th 2和Th 17/Treg比例，从而减轻甲型流感病毒FM1株在小鼠肺部引起的炎症反应。 Toll样受体（TLRs）信号通路也是和呼吸道病毒相关的天然免疫主要信号通路之一， TLRs可以激活 NF⁃κB等转录因子，促进多种与免疫有关的细胞因子及趋化因子的分泌从而引起炎症反应。玉叶金花水提物能抑制感染流感病毒A/FM1/47（H1N1）小鼠血清TNF⁃α、IL⁃6、 IL-1β过表达及肺组织中TLR7、MyD88、NF⁃Κb mRNA及蛋白表达，提示玉叶金花可通过降低TLR7介导的MyD88依赖的信号转导通路活化抑制 NF⁃κB活性，从而减轻炎症风暴，发挥抗流感病毒作用。研究发现，栀子苷通过影响TLR3/TRIF信号通路，降低炎性细胞因子IL-6、TNF⁃α 表达，促进抗病毒因子IFN⁃β 合成，保护A/FM/1/4（H1N1）建立的流感病毒性肺炎小鼠引起的病毒性肺损伤。黄芩苷可通过抑制TLR4/NF⁃κB信号转导途径，降低下游细胞因子IL-6 水平来发挥抑制 HRSV 感染的作用。参考文献： [1]王剑,张萍萍,于健,等.天然药物抗呼吸道病毒活性成分及其作用机制研究进展[J].药学学报,2024,59(04):853-865. [2]杜正彩,郝二伟,韦棪婷,等.中国-东盟传统药用植物抗呼吸道常见病毒研究进展[J].中成药,2022,44(11):3579-3587. 作者简介：小米虫，药品质量研究工作者，长期致力于药品质量研究及药品分析方法验证工作，现就职于国内某大型药物研发公司，从事药品检验分析及分析方法验证。 END 【智药研习社直播预告】来源：CPHI制药在线声明：本文仅代表作者观点，并不代表制药在线立场。本网站内容仅出于传递更多信息之目的。如需转载，请务必注明文章来源和作者。投稿邮箱：Kelly.Xiao@imsinoexpo.com ▼更多制药资讯，请关注CPHI制药在线▼ 点击阅读原文，进入智药研习社~

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