二酮酸类HIV-1整合酶抑制剂的研究进展

HIV-1整合酶催化前病毒DNA整合进入宿主细胞基因组的过程是病毒复制必不可少的步骤,所以抑制HIV-1整合酶活性是治疗HIV-1感染的合理策略。目前已开发了大量HIV-1整合酶抑制剂,其中一些已进入临床研究阶段,从化学结构看,绝大多数已报道的HIV-1整合酶抑制剂属于二酮酸类或其生物电子等排体。该文对近3年来二酮酸类HIV-1整合酶抑制剂的研究进展做简要综述。     

Developing G-quartet oligonucleotides as novel anti-HIV agents: focus on anti-HIV drug design

Recently, a new class of oligonucleotides, forming G-quartet structures, has been developed as novel anti-HIV agents. Several critical structure-activity relationships between HIV-1 integrase and G-quartet oligonucleotides have been demonstrated. In addition the mechanism of the inhibition of HIV-1 integrase by G-quartet oligonucleotides, such as T30695 and its derivatives, has been explored. This review summarises the preliminary studies of developing G-quartet oligonucleotides as novel anti-HIV agents in several aspects including structure-activity relationship, stability-activity correlation, mechanism of HIV-1 integrase inhibition, substitution of phosphorothioates and targeting HIV-1 integrase in infected cells, which, hopefully, could help for developing a novel, efficient anti-HIV agent.     

Developing G-quartet oligonucleotides as novel anti-HIV agents: focus on anti-HIV drug design

Recently, a new class of oligonucleotides, forming G-quartet structures, has been developed as novel anti-HIV agents. Several critical structure-activity relationships between HIV-1 integrase and G-quartet oligonucleotides have been demonstrated. In addition the mechanism of the inhibition of HIV-1 integrase by G-quartet oligonucleotides, such as T30695 and its derivatives, has been explored. This review summarises the preliminary studies of developing G-quartet oligonucleotides as novel anti-HIV agents in several aspects including structure-activity relationship, stability-activity correlation, mechanism of HIV-1 integrase inhibition, substitution of phosphorothioates and targeting HIV-1 integrase in infected cells, which, hopefully, could help for developing a novel, efficient anti-HIV agent.     

Integrase inhibitors for the treatment of HIV infection

HIV-1 integrase catalyzes the insertion of HIV-1 DNA into the genome of the host cell and, therefore, represents a rational target for chemotherapeutic intervention in the treatment of HIV-1 infection. Raltegravir, marketed as Isentress, is the first integrase inhibitor to be approved by the FDA for the treatment of HIV AIDS infection. This review briefly describes the successful medicinal chemistry efforts that culminated in the discovery of raltegravir, and highlights more recent progress that has been made in the field of HIV-1 integrase inhibition.     

Structure-activity relationships of HIV-1 integrase inhibitors--enzyme-ligand interactions

HIV-1 integrase is an essential enzyme for retroviral replication. It is involved in the integration of HIV DNA into host chromosomal DNA and appears to have no functional equivalent in human cells. Therefore it is an attractive and rational target for selective anti-AIDS therapy. A great number of HIV-1 integrase inhibitors have been described in the last decade and numerous reviews have been published. The biochemical mechanism of HIV-1 DNA integration, the enzyme structure and the possible targets for drug intervention have been thoroughly analyzed. Structure-based drug design including both ligand-based (pharmacophore) and target-based (docking) methods has also been discussed. The recent report of the crystal structure of HIV-1 integrase core domain with an inhibitor has given a new boost leading in the last two years to the emergence of diketoacids (DKAs). To date, with the dicaffeoyltartaric acids they are the only two classes of molecules that meet the criteria necessary to be considered lead molecules in the search for clinically useful inhibitors of HIV-1 integrase. After a survey of the function and the structure of this enzyme and the different available assays for the identification of new IN inhibitors, structure-activity relationships of HIV-1 integrase inhibitors that are expected to interact with the active site (or in its vicinity) will be discussed with emphasis on their different proposed mechanisms of action.     

HIV-1整合酶抑制剂体外筛选方法研究进展

整合酶是HIV基因表达和复制所必需的酶,而且宿主细胞内不存在该酶的类似物。因此,HIV-1整合酶已成为设计、筛选抗HIV药物的理想靶点。迄今为止,Raltegravir仍是唯一上市的HIV整合酶抑制剂,而且临床上也已经出现耐药问题。研发新一代整合酶抑制剂非常必要。高通量、高灵敏度、简单易行的筛选方法是研究开发新一代HIV-1整合酶抑制剂的关键。目前,HIV-1整合酶抑制剂筛选方法有多种,各有优缺点,该文将对文献报道的整合酶抑制剂体外筛选方法的最新进展做一介绍。     

Closely related antiretroviral agents as inhibitors of two HIV-1 enzymes, ribonuclease H and integrase: "killing two birds with one stone"

The structures of the catalytic core of two HIV-1 encoded enzymes play a crucial role in the retroviral cycle: integrase and RNase H exhibit striking similarities. These enzymes also share a similar mechanism of catalysis. The homologies between RNase H and integrase led to studying the effect of the RNase H inhibitors on integrase. ODNs aptamers active on RNase H were shown to be strong IN inhibitors. On the contrary, compounds from the diketo acid family were previously known as integrase inhibitors. One compound of this family is able to inhibit the RNase H activity, but has no effect on integrase. Cellular topoisomerase 1 also shares a mechanism similar to that of HIV-1 integrase and RNase H. It has been reported to be present in retroviral particles and to enhance cDNA synthesis. Some topoisomerase inhibitors have been shown to be active on integrase. Moreover, topoisomerase, integrase and RNase H are inhibited by G-rich oligonucleotides. A G-quartet structure is necessary for integrase, but not for topoisomerase inhibition. This suggests that prototype structures can be exploited to develop inhibitors of two related enzymes, such as the RNase H and integrase activities of HIV-1 RT.     

Diketoacid inhibitors of HIV-1 integrase: from L-708,906 to raltegravir and beyond

HIV-1 integrase is one of the three viral enzymes essential to HIV replication. Consequently the development of therapeutics targeting this enzyme has been a major focus of antiretroviral research over the past two decades. Several classes of integrase inhibitors have been identified; of these the diketoacids (DKAs) show greatest promise: raltegravir (Merck & Co) has been approved by the US Food and Drug Administration (FDA) for HIV-1 therapy, while elvitegravir (Gilead Sciences/ Japan Tobacco) has reached phase III clinical trials. This review considers the development of DKA-based inhibitors from early screening studies through to the release of raltegravir. SAR data collated from numerous studies are compared and analysed, shedding light on the geometric and electronic requirements for effective binding to HIV-1 integrase. This information will in turn aid the rational design of future generations of integrase inhibitors.     

Ⅰ型人类免疫缺陷病毒整合酶及其抑制剂研究进展

目的为研究新型Ⅰ型人类免疫缺陷病毒(human immunodeficiency virus type-1,HIV-1)整合酶抑制剂提供参考。方法根据查阅的文献从HIV-1整合酶的结构与功能、HIV-1整合酶的催化机制、HIV-1整合酶抑制剂对整合酶作用环节的影响等方面进行综述。结果HIV-1整合酶是由288个氨基酸残基组成的蛋白质,由病毒pol基因编码,相对分子质量约为32000;HIV-1整合酶抑制剂通过干扰整合酶的多聚化、竞争性结合病毒DNA长末端重复序列、阻断整合酶的"3′-加工"(切割病毒DNA)和"链转移"等影响整合酶的作用。结论利用先进的计算机辅助药物设计手段,通过对现有抑制剂构效关系以及抑制剂与大分子作用方式的研究可以逐步阐明整合酶抑制剂的作用机制;应着眼于寻找高活性的整合酶抑制剂,为治疗艾滋病提供新的途径。     

New developments in diketo-containing inhibitors of HIV-1 integrase

HIV-1 integrase is one of the three enzymes, which are critical for viral replication. It catalyzes the integration of the HIV genome into the cellular chromosome. Since there is no known human homolog to integrase, its inhibition is one of the most promising novel drug targets for anti-retroviral therapy with potential advantage over existing therapies. To date, numerous compounds with diverse structural features have been reported as integrase inhibitors, among which the diketo-containing inhibitors of HIV-1 integrase represent a major lead for anti-HIV drug development. The discovery of diketo acids plays an important role in validating integrase as a legitimate target for treatment of AIDS. In this review, we summarize several drug candidates in clinical trials and new diketo-containing inhibitors of HIV-1 integrase discovered recently.     

多羟基芳香族化合物对HIV-1整合酶的抑制作用

目的研究HIV-1整合酶抑制剂,为艾滋病的治疗提供新作用靶位的抗HIV药物。方法用HIV-1整合酶ELISA法检测3种萘醌类化合物,10种白藜芦醇及其衍生物和7种吡喃香豆素类化合物对整合酶的抑制作用。结果双羟基-1,4-萘醌(NQ-2)对HIV-1整合酶有抑制活性,IC₅₀为78.5 μmol·L^-1,发现萘醌类新化合物NQ-3对HIV-1整合酶的抑制作用优于NQ-2,IC₅₀为37.2 μmol·L^-1。用分步测定法发现NQ-2主要抑制HIV-1整合酶的链转移活性,而NQ-3则对装配和链转移都有较强的抑制。结论萘醌类化合物(NQ-2,3)对HIV-1整合酶有抑制作用,NQ-3为新化合物值得进一步研究。     

HIV-1整合酶抑制剂的研究进展

HIV-1整合酶是设计抗艾滋病药物的理想靶点，综述了HIV-1整合酶抑制剂的研究进展。     

Binding mode prediction of strand transfer HIV-1 integrase inhibitors using Tn5 transposase as a plausible surrogate model for HIV-1 integrase

The crystal structure of Tn5 transposase-DNA complex was used in docking experiments to predict binding modes of HIV-1 integrase strand transfer inhibitors (INSTIs). In fact, the identification of HIV-1 integrase inhibitors from an in vitro screen using Tn5 transposase as the target has been recently reported. Our results suggest the utility of this protein as a useful surrogate model for IN and also for in silico screening, in the search for new potential INSTIs.     

Raltegravir (MK-0518): an integrase inhibitor for the treatment of HIV-1

In the developed world, access to highly active antiretroviral therapy (HAART) has led to significant reductions in the morbidity and mortality attributed to HIV/AIDS. However, the continual emergence of HIV-1 strains resistant to currently available classes of antiretrovirals highlights the need to develop agents with novel mechanisms of action. Successful completion of the HIV-1 viral life cycle depends in part on the integration of complementary DNA mediated by the enzyme HIV-1 integrase, one of three essential enzymes encoded in the viral genome. The integrase inhibitors have demonstrated the ability to act specifically at the strand transfer step during integration, making HIV-1 integrase a valid and attractive chemotherapeutic target for the treatment of HIV/AIDS. In clinical trials, raltegravir has been shown to be a potent drug with a pharmacokinetic profile that supports a twice-daily dosing schedule. In addition, it has demonstrated a favorable side-effect profile in treatment-naive and -experienced patients and a subset of heavy treatment-experienced patients have been able a achieve virologic suppression with raltegravir as part of combination therapy despite limited treatment options. In October 2007, raltegravir was approved by the U.S. Food and Drug Administration (FDA) for the treatment of HIV-1 as part of combination antiretroviral therapy in treatment-experienced patients-providing an additional option for the management of the HIV-1 infected individual.     

Preferential inhibition of the magnesium-dependent strand transfer reaction of HIV-1 integrase by alpha-hydroxytropolones

Integration is a crucial step in the life cycle of human immunodeficiency virus type 1 (HIV-1); therefore, inhibitors of HIV-1 integrase are candidates for antiretroviral therapy. Two 7-hydroxytropolone derivatives (alpha-hydroxytropolones) were found to inhibit HIV-1 integrase. A structure-activity relationship investigation with several tropolone derivatives from The National Cancer Institute compound repository demonstrated that the 7-hydroxy group is essential for integrase inhibition. alpha-Hydroxytropolones preferentially inhibit strand transfer and are inhibitory both in the presence of magnesium or manganese. Lack of inhibition of disintegration in the presence of magnesium coupled with results from different cross-linking assays suggests alpha-hydroxytropolones as interfacial inhibitors. We propose that alpha-hydroxytropolones chelate the divalent metal (Mg2+ or Mn2+) in the enzyme active site. The most active compound against HIV-1 integrase in biochemical assays [2,4,6-cycloheptatrien-1-one, 2,7-dihydroxy-4-isopropyl (NSC 18806) IC50 = 4.8 +/- 2.5 microM] exhibits weak cytoprotective activity against HIV-1(IIIB) in a cell-based assay. alpha-Hydroxytropolones represent a new family of inhibitors for the development of novel drugs against HIV infection.     

Design and synthesis of novel N-hydroxy-dihydronaphthyridinones as potent and orally bioavailable HIV-1 integrase inhibitors

HIV-1 integrase (IN) is one of three enzymes encoded by the HIV genome and is essential for viral replication, and HIV-1 IN inhibitors have emerged as a new promising class of therapeutics. Recently, we reported the synthesis of orally bioavailable azaindole hydroxamic acids that were potent inhibitors of the HIV-1 IN enzyme. Here we disclose the design and synthesis of novel tricyclic N-hydroxy-dihydronaphthyridinones as potent, orally bioavailable HIV-1 integrase inhibitors displaying excellent ligand and lipophilic efficiencies.