阿德福韦酯的合成工艺优化及质量控制

阿德福韦酯是开环膦酸核苷酐类抗病毒药物,是阿德福韦的酯类前体药物,具有广谱的抗病毒活性。阿德福韦酯合成工艺中的酯化反应,质量不稳定,收率较低。在现有合成工艺路线文献报道的基础上,通过对反应温度、反应时间、投料比等因素的研究,重新优化合成工艺,并进行质量控制。采用正交设计法,重点考察反应温度(A)、投料比(B)、反应时间(C)3个因素对阿德福韦酯酯化反应的影响。通过实验研究,确定了阿德福韦酯酯化反应的最佳工艺条件为A2B1C1,提高了产品质量和收率。     

艾滋病免费抗病毒药物的不良反应

目前已有29种抗艾滋病病毒药物通过美国FDA的批准,并应用于临床.抗艾滋病病毒药物分为:核苷类逆转录酶抑制剂(NRTI),非核苷类逆转录酶抑制剂(NNRTI),蛋白酶抑制剂(PI),融合抑制剂(FI).我国目前免费抗病毒药物有NRTI、NNRTI和PI,共7种药.现将其不良反应综述如下.     

艾滋病免费抗病毒药物的不良反应

目前已有29种抗艾滋病病毒药物通过美国FDA的批准,并应用于临床。抗艾滋病病毒药物分为：核苷类逆转录酶抑制剂（NRTI）,非核苷类逆转录酶抑制剂（NNRTI）,蛋白酶抑制剂（PI）,融合抑制剂（FI）。我国目前免费抗病毒药物有NRTI、NNRTI和PI,共7种药。现将其不良反应综述如下。     

核苷二苯基磷酸酯的合成及大鼠体内药物动力学

AZT的5'-二苯基系列磷酸酯衍生物在体外抗病毒实验中显示了良好的抗HIV病毒活性,具有开发为新型核苷类抗病毒药物的潜力.本文采用PCl3-锅法合成了系列核苷二苯基磷酸酯,并对其纯化后的化合物进行大鼠体内药物动力学规律评价.结果显示该系列衍生物的动力学表现和苯基上取代基的性质有直接联系,且均能改善对AZT的释放,有作为临床抗艾滋病治疗剂的可能.     

抗病毒药物及作用机制

通过阅读大量的文献资料,介绍有关目前临床应用的抗病毒药物的作用机制、核苷类药物类型、抗流感病毒神经氨酸酶抑制剂及正在研发的抗疱疹病毒蛋白酶抑制剂。     

我省成功地合成三氮唑核苷

浙江省德清生物技术中试基地,最近采用新工艺合成三氮唑核苷,该项成果已通过省科委、省医药管理局联合鉴定。三氮唑核苷是七十年代美国开发的新药。它对多种RNA和DNA病毒均有明显抑制作用,至今该药是合成的抗病毒剂中效果最佳的广谱抗病毒药物之一,特别是对流感、副流感、腺病毒肺炎、口腔和眼疱疹等病毒疗效极佳。近年国内报道该药对流行性出血热疗效显著,被誉为出血热的“克星”。国     

蛋白酶抑制剂引起血小板减少1例

艾滋病属于新发传染病,在世界流行的时间不长,但其危害严重,临床上使用的艾滋病抗病毒药物主要包括四类,即核苷类逆转录酶抑制剂(NRTIs)、非核苷类逆转录酶抑制剂(NNRTIs)、蛋白酶抑制剂(PIs)和融合抑制剂(FIs).这四类抗病毒药物中,以蛋白酶抑制剂对血液系统的影响较大,本文报道了一例血友病患者使用蛋白酶抑制剂引起血小板减少的情况.     

蛋白酶抑制剂引起血小板减少1例

艾滋病属于新发传染病,在世界流行的时间不长,但其危害严重,临床上使用的艾滋病抗病毒药物主要包括四类,即核苷类逆转录酶抑制剂（NR-TIs）、非核苷类逆转录酶抑制剂（NNRTIs）、蛋白酶抑制剂（PIs）和融合抑制剂（FIs）。这四类抗病毒药物中,以蛋白酶抑制剂对血液系统的影响较大,本文报道了一例血友病患者使用蛋白酶抑制剂引起血小板减少的情况。     

屈氟尿苷及其类似物与腺嘌呤核苷间氢键作用的探讨

研究取代基对核苷分子构成的氢键复合物稳定性的影响,对于推动新型抗病毒药物的研发工作有着重要的意义.在M06-2X/6-31+G(d,p)水平上对9种不同的屈氟尿苷或其取代类似物与腺嘌呤核苷构成的氢键复合物的结构进行了预测,并在M06-2X/aug-cc-pVTZ水平上对复合物相对稳定性进行了探讨.研究发现,该类氢键复合物中N—H…N氢键作用最强,N—H…O=C次之,C—H…O=C最弱.基于模拟结果,嘧啶环C5上的吸电子取代基使嘧啶环作为氢键质子供体的能力增强,从而加强了它与腺嘌呤核苷间氢键作用,供电子取代基使嘧啶环作为氢键质子供体的能力减弱,从而削弱了它与腺嘌呤核苷间氢键作用.推测F、CN、Cl和SO_3H取代的脱氧核苷类化合物很可能成为新的抗病毒药物而引起广泛关注.     

S胞苷发酵生产的育种及发酵条件优化策略

胞苷主要用于生产抗肿瘤、抗病毒药物的中间体,随着深入研究,天然的嘧啶核苷需求量加大,根据胞苷的生物合成途径及其代谢调节机制和代谢调控理论,重点阐述了胞苷生产菌的育种及培养条件优化策略,以期为胞苷发酵生产提供理论指导.     

9-(2-hydroxyethoxymethyl) guanine activity against viruses of the herpes group.

Of a series of nucleoside analogues synthesised, 9-(2-hydroxyethoxymethyl) guanine was found to have marked antiviral activity in animal models of herpes virus infections, associated with very low toxicity.     

Crystal structure of a concentrative nucleoside transporter from Vibrio cholerae at 2.4 Å

Nucleosides are required for DNA and RNA synthesis, and the nucleoside adenosine has a function in a variety of signalling processes. Transport of nucleosides across cell membranes provides the major source of nucleosides in many cell types and is also responsible for the termination of adenosine signalling. As a result of their hydrophilic nature, nucleosides require a specialized class of integral membrane proteins, known as nucleoside transporters (NTs), for specific transport across cell membranes. In addition to nucleosides, NTs are important determinants for the transport of nucleoside-derived drugs across cell membranes. A wide range of nucleoside-derived drugs, including anticancer drugs (such as Ara-C and gemcitabine) and antiviral drugs (such as zidovudine and ribavirin), have been shown to depend, at least in part, on NTs for transport across cell membranes. Concentrative nucleoside transporters, members of the solute carrier transporter superfamily SLC28, use an ion gradient in the active transport of both nucleosides and nucleoside-derived drugs against their chemical gradients. The structural basis for selective ion-coupled nucleoside transport by concentrative nucleoside transporters is unknown. Here we present the crystal structure of a concentrative nucleoside transporter from Vibrio cholerae in complex with uridine at 2.4??. Our functional data show that, like its human orthologues, the transporter uses a sodium-ion gradient for nucleoside transport. The structure reveals the overall architecture of this class of transporter, unravels the molecular determinants for nucleoside and sodium binding, and provides a framework for understanding the mechanism of nucleoside and nucleoside drug transport across cell membranes.     

头孢菌素类抗生素的研究进展

头孢菌素类抗生素药物是临床上用于治疗细菌感染所导致疾病的常用药物,已发展到第4代.目前头孢菌素类药物的研究热点在于寻找对耐药的革兰氏阳性致病菌敏感,尤其是对耐甲氧西林金葡萄球菌(MRSA)敏感的头孢烯酸类化合物及对高活性化合物进行结构修饰,改善其药学性质.就研发中的头孢菌素类化合物的结构、抗菌谱和抗菌活性作一简要综述.     

2022年全球新冠肺炎疫苗和药物研究热点回眸

新冠肺炎疫情给人类生活带来极大影响。疫情发生后，全球科研机构和制药公司迅速应对，加紧研发疫苗和抗病毒药物。2022年，多个mRNA创新性疫苗、抗病毒中和抗体、小分子抗病毒药物等相继问世。然而，随着多种新冠病毒变异株的相继出现，新冠肺炎疫苗、中和抗体以及小分子药物的有效性大幅降低，不断对新冠肺炎疫苗和药物的开发提出新的挑战。结合文献和商业数据库信息，对当前新冠肺炎疫苗和药物的研发进展进行综述。截至2022年11月，全球已批准或EUA疫苗和药物各30余款，多款疫苗和药物处于临床试验中，中国在新冠疫苗和抗新冠药物研发方面走在世界前列。     

HBV基因型与干扰素及核苷类似物抗病毒治疗疗效的关系

目的:介绍乙型肝炎病毒(HBV)基因型与抗病毒治疗疗效关系的最新进展.方法:综合分析近年国内外有关HBV基因型与抗病毒治疗疗效关系的文献资料.结果:感染HBV基因型A的慢性乙型肝炎患者对干扰素治疗的应答率高于基因型D,基因型B高于基因型C;HBV基因型与核苷类似物治疗疗效的关系目前尚存争议;基因型E、F、G、H是否影响抗病毒疗效报道较少.结论:HBV基因型与抗病毒治疗疗效存在一定的相关性;HBV基因型的研究将有助于临床抗病毒治疗方案的优化.     

A protein kinase homologue controls phosphorylation of ganciclovir in human cytomegalovirus-infected cells.

Human cytomegalovirus (HCMV) is a major pathogen in immunosuppressed individuals, including patients with acquired immune deficiency syndrome. The nucleoside analogue ganciclovir (9-(1,3-dihydroxy-2-propoxymethyl)-guanine) is one of the few drugs available to treat HCMV infections, but resistant virus is a growing problem in the clinic and there is a critical need for new drugs. The study of ganciclovir-resistant mutants has indicated that the selective action of ganciclovir depends largely on virus-controlled phosphorylation in HCMV-infected cells. The enzyme(s) responsible have not been identified. Here we report that the HCMV gene UL97, whose predicted product shares regions of homology with protein kinases, guanylyl cyclase and bacterial phosphotransferases, controls phosphorylation of ganciclovir in HCMV-infected cells. A four-amino-acid deletion of UL97 in a conserved region, which in cyclic AMP-dependent protein kinase participates in substrate recognition, causes impaired ganciclovir phosphorylation. The implications of these results for antiviral drug development and drug resistance are discussed.     

Antiviral treatment is more effective than smallpox vaccination upon lethal monkeypox virus infection

There is concern that variola virus, the aetiological agent of smallpox, may be used as a biological weapon. For this reason several countries are now stockpiling (vaccinia virus-based) smallpox vaccine. Although the preventive use of smallpox vaccination has been well documented, little is known about its efficacy when used after exposure to the virus. Here we compare the effectiveness of (1) post-exposure smallpox vaccination and (2) antiviral treatment with either cidofovir (also called HPMPC or Vistide) or with a related acyclic nucleoside phosphonate analogue (HPMPO-DAPy) after lethal intratracheal infection of cynomolgus monkeys (Macaca fascicularis) with monkeypox virus (MPXV). MPXV causes a disease similar to human smallpox and this animal model can be used to measure differences in the protective efficacies of classical and new-generation candidate smallpox vaccines. We show that initiation of antiviral treatment 24 h after lethal intratracheal MPXV infection, using either of the antiviral agents and applying various systemic treatment regimens, resulted in significantly reduced mortality and reduced numbers of cutaneous monkeypox lesions. In contrast, when monkeys were vaccinated 24 h after MPXV infection, using a standard human dose of a currently recommended smallpox vaccine (Elstree-RIVM), no significant reduction in mortality was observed. When antiviral therapy was terminated 13 days after infection, all surviving animals had virus-specific serum antibodies and antiviral T lymphocytes. These data show that adequate preparedness for a biological threat involving smallpox should include the possibility of treating exposed individuals with antiviral compounds such as cidofovir or other selective anti-poxvirus drugs.     

5-取代嘧啶核苷及其抗疱疹病毒活性

介绍了一些具有显著抗疱疹病毒活性的5-取代嘧啶类核苷衍生物以及它们的作用机理,指出了不同取代基对相应化合物生物活性的影响,并对部分化合物进行了构效关系总结.     

硼氢化立体选择性还原制备拉米夫定的研究

在对核苷类抗病毒药物拉米夫定的制备进行文献综述的基础上,提出一条立体选择硼氢化还原的合成路线合成了拉米夫定．反应中形成的六元环过渡态结构有效抑制消旋化,使得反应过程工艺简单,产品纯度好,收率高,完全符合作为原料药的使用要求．     

多金属氧酸盐及其衍生物在药物方面的研究进展

多酸和基于多酸的化合物由于其特殊结构和性能,成为非常有前途的金属药物。讨论了多酸及其衍生物,特别是多酸基有机无机杂化物在抗肿瘤、抗病毒和抗细菌方面的研究进展。