Targeting SARS-CoV-2 PLpro for COVID-19 treatment

针对 SARS-CoV-2 PLpro 进行 COVID-19 治疗

• 批准号: 10604688
• 负责人: Rui Xiong
• 金额: $ 64.13万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-22 至 2027-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10604688
• 关键词: 2019-nCoV; Active Sites; Address; Affinity; Animal Model; Antiviral Agents; Binding; Binding Sites; Biochemical; Biological Assay; Biological Availability; COVID-19 pandemic; COVID-19 treatment; Caspase; Cell model; Cells; Complement; Complex; Crystallization; Cysteine; Data; Development; Disease Outbreaks; Distal; Dose; Drug Exposure; Drug Kinetics; Drug usage; Ensure; Enzyme Inhibition; Future; Glycine; Goals; Human; Immune; Impairment; In Vitro; Innate Immune Response; Interferon Type I; Intraperitoneal Injections; Lead; Ligand Binding; Lung; Modeling; Mus; Oral; Papain; Peptide Hydrolases; Permeability; Pharmaceutical Chemistry; Pharmaceutical Preparations; Polyproteins; Positioning Attribute; Property; Protease Inhibitor; Research; Roentgen Rays; Role; SARS-CoV-2 infection; SARS-CoV-2 inhibitor; Series; Site; Solubility; Structure; Surface; Testing; Toxicology; Treatment Efficacy; Triage; Vaccination; Vaccines; Variant; Viral; Viral Load result; Viral Proteins; Virus; Virus Replication; X-Ray Crystallography; anti-viral efficacy; antiviral drug development; base; design; drug candidate; drug discovery; expectation; improved; in silico; in vivo; inflammatory marker; inhibitor; inhibitor therapy; insight; intraperitoneal; mouse model; nanomolar; novel; pandemic disease; pharmacokinetics and pharmacodynamics; pre-clinical; programs; prophylactic; scaffold; small molecule; socioeconomics; targeted agent; therapeutic target

ABSTRACT The COVID-19 pandemic, caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has caused profound socioeconomic challenges for humankind. Antiviral agents blocking SARS-CoV-2 viral replication that complement vaccination are urgently needed to stop the current pandemic and to avoid potential future outbreaks. The papain-like protease (PLpro), an essential cysteine protease that regulates viral replication and host immune sensing, is a promising antiviral target against SARS-CoV-2. However, the rapid development of potent PLpro inhibitors has been hindered by limited draggable interactions at the active site due to restricted P1 and P2 sites with glycine recognition. To address these challenges, we have investigated novel, druggable binding sites, distal to the active site, using structure-guided design and X-ray crystallography. These efforts led to a series of 2-phenylthiophene-based inhibitors with low nanomolar potency. Crystal structures revealed that these potent SARS-CoV-2 PLpro inhibitors engage with a novel ligand-binding site, the “BL2 groove”, leading to slower off-rates, improved binding affinities, and low micromolar antiviral potency in SARS-CoV-2-infected human cells. Moreover, these inhibitors showed good microsomal stability and in vivo exposure after intraperitoneal (IP) administration. Building on these encouraging preliminary data, we propose in this project to further optimize and develop these novel PLpro inhibitors to achieve in vivo antiviral efficacy. We propose: Aim 1) to optimize our lead PLpro inhibitors for improved potency and drug- likeness properties using structure-guided design; Aim 2) to evaluate and triage PLpro inhibitors based on biochemical, ADME, and antiviral assays; Aim 3) to assess the PK/PD profile of top inhibitors and to establish in vivo antiviral efficacy. Completion of the research will lead to small molecules suitable for development as drug candidates to treat SARS-CoV-2.

抽象的 由新型严重急性呼吸综合征冠状病毒 2 引起的 COVID-19 大流行 （SARS-CoV-2）给人类带来了深刻的社会挑战。 阻断 SARS-CoV-2 病毒复制，迫切需要补充疫苗接种来阻止 当前的大流行并避免未来潜在的爆发。 一种调节病毒复制和宿主免疫感应的必需半胱氨酸蛋白酶，是一种 然而，有效的 PLpro 的快速发展。 由于限制性的限制，抑制剂在活性位点受到有限的可拖动相互作用的阻碍 具有甘氨酸识别的 P1 和 P2 位点 为了解决这些挑战，我们进行了研究。 采用结构引导设计和 X 射线，位于活性位点远端的新型可药物结合位点 这些努力产生了一系列基于 2-苯基噻吩的抑制剂。 晶体结构揭示了这些有效的 SARS-CoV-2 PLpro 抑制剂。 与新的配体结合位点“BL2 凹槽”接合，导致解离速率减慢，改善 SARS-CoV-2 感染的人类细胞中的结合亲和力和低微摩尔抗病毒效力。 此外，这些抑制剂表现出良好的微粒体稳定性和体内暴露后 基于这些令人鼓舞的初步数据，我们提出腹膜内（IP）给药。 该项目旨在进一步优化和开发这些新型PLpro抑制剂以实现体内抗病毒 我们建议：目标 1) 优化我们的主要 PLpro 抑制剂，以提高效力和药物- 使用结构指导设计的相似性；目标 2) 评估和分类 PLpro 抑制剂 基于生化、ADME 和抗病毒检测；目标 3) 评估顶级药物的 PK/PD 概况 抑制剂并确定体内抗病毒功效的研究的完成将带来小成果。 适合开发作为治疗 SARS-CoV-2 候选药物的分子。