'Fat' Nucleosides and Nucleotides

“脂肪”核苷和核苷酸

• 批准号: 6861031
• 负责人: Ramachandra S Hosmane
• 金额: $ 33.54万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE COUNTY
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-07-15 至 2007-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6861031
• 关键词: Fat; Nucleosides; Nucleotides

DESCRIPTION (provided by applicant): Ring-expanded (Fat) purine nucleosides and nucleotides are of chemical, biochemical, biophysical and medicinal interest. From a chemical standpoint, their synthesis, structure, stability, acid-base properties, aromaticity, and tautomeric equilibria are interesting. From a biochemical perspective, they are an abundant source of substrates or inhibitors of enzymes of purine metabolism, as well as of those requiring energy cofactors. In biophysical terms, they are potentially excellent probes for nucleic acid structure, function, and metabolism. Medicinally, they offer a unique source of opportunities for anticancer and antiviral therapy. With regard to this latter aspect, a number of "fat" nucleosides have recently exhibited potent, broad-spectrum antiviral and anticancer activities in vitro with little toxicity, if any, to the host cell lines. The antiviral activities include hepatitis B and C virus (HBV and HCV), West Nile virus (WNV), Epstein-Barr virus (EBV), Vericella Zoster virus (VZV), Japanese Encephalitis virus (JEV), Rhino virus (RV), Herpes Simplex (HSV-1 and HSV-2) viruses, and Measles virus (MV). The in vitro anticancer activities include leukemia, lung, colon, CNS, melanoma, ovarian, renal, prostate, and breast cancers. However, this proposal specifically focuses on the West Nile Virus (WNV) in light of the current health scare of this virus in US. The proposal concerns mechanistic investigations of viral replication employing a few "fat" nucleosides that have exhibited potent in vitro anti-WNV activity. Two specific modes viral inhibition, which are deemed most viable, will be explored. Appropriate synthetic strategies have been put in place for further structural modifications of "fat" nucleosides and nucleotides, contingent upon the outcome of the proposed mechanistic investigations, so as to eventually discover most potent antivirals against WNV with dismal, if any, human toxicity.

描述（由申请人提供）：环形膨胀（脂肪）嘌呤核苷和核苷酸是化学，生化，生物物理和药物兴趣的。从化学的角度来看，它们的合成，结构，稳定性，酸碱特性，芳香性和互变异体平衡很有趣。从生化的角度来看，它们是嘌呤代谢酶的底物或抑制剂的丰富来源，也是需要能量辅助因子的酶的抑制剂。用生物物理术语来说，它们是核酸结构，功能和代谢的潜在优秀探针。在药物上，它们为抗癌和抗病毒疗法提供了独特的机会。关于后一个方面，许多“脂肪”核苷最近在体外表现出有效的，广谱的抗病毒和抗癌活性，对宿主细胞系的毒性很小（如果有的话）。抗病毒活性包括丙型肝炎和C病毒（HBV和HCV），西尼罗河病毒（WNV），爱泼斯坦 - 巴尔病毒（EBV），vericella zoster病毒（VZV），日本脑炎病毒（JEV），犀牛病毒（RV），Simplex Simplex（HSV-1和HSV-1和HSV）病毒量。体外抗癌活性包括白血病，肺，结肠癌，CNS，黑色素瘤，卵巢，肾脏，前列腺和乳腺癌。但是，鉴于美国目前对这种病毒的健康恐惧，该提案特别关注西尼罗河病毒（WNV）。该提案涉及对病毒复制的机理研究，该病毒复制采用了一些表现出有效体外抗WNV活性的“脂肪”核苷。将探索两种特定的模式病毒抑制，这些模式被认为是最可行的。已经制定了适当的合成策略，以进一步对“脂肪”核苷和核苷酸的结构修饰，取决于提议的机械研究的结果，以最终发现对WNV的最有效的抗病毒药，即使有任何人类的毒性。

项目成果

Characterization of Oral Immunity in Cases and Close Household Contacts Exposed to Andes Orthohantavirus (ANDV).

• DOI: 10.3389/fcimb.2020.557273
• 发表时间: 2020
• 期刊: Frontiers in cellular and infection microbiology
• 影响因子: 5.7
• 作者: Martinez-Valdebenito C;Andaur C;Angulo J;Henriquez C;Ferrés M;Le Corre N
• 通讯作者: Le Corre N

Inhibition of adenosine deaminase by novel 5:7 fused heterocycles containing the imidazo[4,5-e][1,2,4]triazepine ring system: a structure-activity relationship study.

含有咪唑并[4,5-e][1,2,4]三氮杂环系统的新型 5:7 稠合杂环对腺苷脱氨酶的抑制：构效关系研究。

• DOI: 10.1021/jm0304257
• 发表时间: 2004
• 期刊: Journal of medicinal chemistry.
• 作者: Reayi,Ayub;Hosmane,RamachandraS
• 通讯作者: Hosmane,RamachandraS

Synthesis and in vitro anti-hepatitis B and C virus activities of ring-expanded ('fat') nucleobase analogues containing the imidazo[4,5-e][1,3]diazepine-4,8-dione ring system.

含有咪唑并[4,5-e][1,3]二氮杂-4,8-​​二酮环系统的扩环（“脂肪”）核碱基类似物的合成及其体外抗乙型和丙型肝炎病毒活性。

• DOI: 10.1016/j.bmcl.2005.09.015
• 发表时间: 2005
• 期刊: Bioorganic & medicinal chemistry letters.
• 作者: Zhang,Peng;Zhang,Ning;Korba,BrentE;Hosmane,RamachandraS
• 通讯作者: Hosmane,RamachandraS

Structure-activity relationship studies on anti-HCV activity of ring-expanded ('fat') nucleobase analogues containing the imidazo[4,5-e][1,3]diazepine-4,8-dione ring system.

• DOI: 10.1016/j.bmcl.2007.01.085
• 发表时间: 2007-04
• 期刊: Bioorganic & medicinal chemistry letters
• 影响因子: 2.7
• 作者: Peng Zhang;Ning Zhang;B. Korba;R. Hosmane

Application of real-time PCR for testing antiviral compounds against Lassa virus, SARS coronavirus and Ebola virus in vitro.

• DOI: 10.1016/j.antiviral.2004.05.001
• 发表时间: 2004-09
• 期刊: Antiviral research
• 影响因子: 7.6
• 作者: Günther S;Asper M;Röser C;Luna LK;Drosten C;Becker-Ziaja B;Borowski P;Chen HM;Hosmane RS
• 通讯作者: Hosmane RS