SELF-MASKED ALDEHYDES AS INHIBITORS OF THE CYSTEINE PROTEASES 3CL PROTEASE, CATHEPSIN L, AND CRUZAIN

自掩蔽醛作为半胱氨酸蛋白酶 3CL 蛋白酶、组织蛋白酶 L 和 CruzAIN 的抑制剂

基本信息

批准号：
10355007
负责人：
Thomas Meek
金额：
$ 23.32万
依托单位：
TEXAS A&M AGRILIFE RESEARCH
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-11-04 至 2023-10-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10355007
关键词：
2019-nCoV Active Sites Address Aldehydes Animal Model Anti-Infective Agents Autopsy Binding Proteins Biological Assay COVID-19 COVID-19 pandemic COVID-19 patient COVID-19 treatment Caspase Cathepsin L Cell model Cells Central America Cessation of life Chagas Disease Communicable Diseases Coronavirus Crystallization Cysteine Cysteine Proteinase Inhibitors Drug Kinetics Drug Targeting Enzyme Inhibitor Drugs Enzymes Evaluation Homologous Gene Human Individual Infection Lung Maintenance Malaria Mammalian Cell Masks Medical Metabolic Microsomes Modification Parasites Peptide Hydrolases Peptides Pharmaceutical Chemistry Pharmaceutical Preparations Phase II Clinical Trials Plasma Play Prodrugs Property Proteins Publications Reporting Risk Role SARS-CoV-2 infection SARS-CoV-2 inhibitor SARS-CoV-2 variant Sampling Series Severities Solubility South America Structure Therapeutic Agents Time Toxic effect Trypanosoma cruzi Vaccines aqueous covalent bond cruzain design human disease improved in vitro Assay inhibitor molecular modeling nanomolar novel novel therapeutics oxidation scaffold

项目摘要

PROJECT SUMMARY Cysteine proteases play essential roles in the causative agents of numerous infectious diseases, including malaria, Chagas disease (CD, caused by the parasite Trypanosoma cruzi), and COVID- 19 (caused by the coronavirus SARS-CoV-2). There are neither vaccines nor well-tolerated therapies available for CD, which results in 50,000 annual deaths in Central and South America, with an estimated 300,000 infected individuals in the US. Cruzain is a cysteine protease that is essential to the establishment and maintenance of human infection by T. cruzi. By February 2021, the COVID-19 pandemic has resulted in 103 million cases worldwide and 2.2 million deaths. Despite the recent arrival of effective vaccines, the emergence of new variants of SARS-CoV-2 may render them less effective over time. Accordingly, the discovery of new therapeutic agents to treat COVID-19 remains a critical, unmet medical need. We recently showed that K11777, an irreversible, covalent inactivator of both cruzain and cathepsin L, potently blocked SARS-CoV-2 infection of mammalian cells by inactivation of the cysteine protease cathepsin L. Consequently, since then K11777 has advanced to Phase 2 clinical trials for the treatment of COVID-19. A recent publication reported that cathepsin L was significantly upregulated in lung autopsy samples from COVID-19 patients, suggesting that this CP not only has a key role in CoV-2 cell entry but also in the severity of human disease. Infection by SARS-CoV-2 requires the action of coronaviral protease 3CL protease (3CL-PR); also a cysteine protease, and consequently is an important drug target for COVID-19. Our approach is to identify inhibitors of cysteine proteases which form reversible covalent bonds with the invariant active-site cysteines of these enzymes. Ideally, selection of an appropriate peptide scaffold for such an inhibitor would provide a compound that potently inhibits more than one CP. Aldehydes are exceptionally potent, covalent, but reversible, inhibitors of cysteine proteases, despite the risk associated with their reactivity and metabolic instability. Here, we seek to re-address aldehydes as potent, reversible enzyme inhibitors by modifying them as intramolecular lactols, or “self-masked” aldehydes (SMAIs). The objective of this proposal is to design, synthesize, and evaluate new SMAIs, including prodrug forms, as novel inhibitors of these three CP drug targets, and evaluate their anti-infective properties in cellular models of CD and COVID-19. We will improve the drug-like properties of these new inhibitors in terms of pharmacokinetics, metabolic stability, and identify additional series of SMAIs. We will utilize prodrug forms of these inhibitors that provide enhanced metabolic stability from which active inhibitors should be released intercellularly upon enzymatic modification.

项目摘要半胱氨酸蛋白酶在多种传染病的病因中起着重要作用，纳入疟疾，chagas病（CD，由寄生虫锥虫引起）和covid- 19（由冠状病毒SARS-COV-2引起）。可用于CD的疗法，在南美中部导致每年50,000例死亡，估计在美国有30万个受感染的人。克鲁兹（T. Cruzi）对人类感染的建立和维持至关重要。 COVID-19大流行已导致全球1.03亿例病例和220万例死亡。尽管有效疫苗最近到来，但SARS-COV-2的新变体的出现随着时间的流逝，它们的效率较低。为了治疗Covid-19仍然是至关重要的，我们最近表明K11777 Cruzain和组织蛋白酶L的不可逆转，共价灭活剂，有效地阻止了SARS-COV-2 通过失活半胱氨酸蛋白酶组织蛋白酶L.感染哺乳动物细胞。因此，从那时起，K11777已晋升为2期临床试验，以治疗Covid-19 出版物报道，在肺尸检样本中，组织蛋白酶L显着上调 COVID-19患者，表明该CP不仅在COV-2细胞进入中具有关键作用，而且在人类疾病的严重程度。蛋白酶3Cl蛋白酶（3Cl-pr）也是半胱氨酸蛋白酶 COVID-19的药物靶标。与TESE酶的一些不变的活性位点半胱氨酸的可逆共价键。选择适当的肽支架作为这种继承者将提供一种化合物有效抑制一个以上的CP。半胱氨酸蛋白酶的抑制剂，尽管与反应性和代谢相关的风险不稳定。将它们修饰为分子内乳糖，或“自我掩盖”醛（SMAIS）该建议是设计，合成和评估新的SMAI，倾斜前药形式，作为新颖的形式三种CP药物靶标的抑制剂，并评估其在细胞中的抗感染特性 CD和COVID模型，我们将改善新的新型抑制剂的药物样药代动力学的术语，代谢稳定性并确定了其他SMAIS 利用抑制剂的前药形式，这些形式提高了代谢稳定性活性抑制剂应在酶促修饰后释放互球。