HIV蛋白酶抑制剂与细胞凋亡

HIV感染人体后造成大量CD4 + T淋巴细胞的凋亡 ,从而破坏免疫系统 ,使机体无法抵抗病毒的入侵 ,导致免疫缺陷。目前的药物靶点都针对病毒本身 ,无法清除体内储存病毒的感染细胞 ,而HIV蛋白酶抑制剂治疗HIV/AIDS患者后可以减少HIV感染引起的细胞凋亡 ,帮助机体恢复免疫功能 ,并且这种作用与其抑制病毒的作用是相独立的 ,这提示了可以通过免疫重建的策略来治疗AIDS。本文综述了HIV蛋白酶抑制剂的研究和发展概况 ,其作用特点以及对细胞凋亡的影响。明确HIV蛋白酶抑制剂与细胞凋亡的关系 ,可以启发新的思路从细胞着手 ,通过恢复机体的免疫能力来对抗病毒 ,从根本上治疗AIDS。     

Prodrugs of HIV protease inhibitors

Despite the efficiency of the present polytherapies against AIDS, HIV replication continues indicating difficulties in drug adherence, drug-drug interactions, resistance issues, and the existence of reservoirs or sanctuaries for the virus. Moreover, most of the current FDA-approved HIV protease inhibitors (PIs) display disadvantageous physicochemical and pharmacological properties such as low water solubility, low oral bioavailability and/or low level of penetration into the HIV sanctuaries resulting from their in vivo binding to the plasma proteins and to the Multi-Drug-Resistant P-glycoprotein, their rapid metabolization and inactivation by the liver cytochrome P450 enzymes. To overcome these suboptimal pharmacokinetics, high daily doses must be ingested, which complicate patient adherence to the prescribed regimen and contribute to the appearance of serious long-term metabolic complications and to the decrease of the viral treatment outcome. Another attractive alternative aimed at improving the safety, pharmacokinetics, and therapeutic potency of the current PIs is to modify these PIs into pharmacologically inactive prodrugs which are converted in vivo into their parent active drug. The present review is dedicated to the different prodrug approaches, including the "lipophilic", "hydrophilic", "active transport" and "double-drug" prodrug strategies, which have been applied more particularly to the current HIV PIs used in clinic. Among the strategies explored up to now, the most successful one was the "hydrophilic" prodrug approach which has led to the discovery of fosamprenavir, a phosphate ester prodrug of amprenavir, which has reached phase III clinical trials. This success gives strong support for the search of PI prodrugs as a therapeutic alternative in addition to the development of new and well-tolerated PIs.     

Antidystonic efficacy of gamma-aminobutyric acid uptake inhibitors in the dtsz mutant

In the dtsz mutant hamster, a model of paroxysmal dyskinesia in which dystonic episodes occur in response to stress, previous studies suggested that retarded development of gamma-aminobutyric acid (GABA)ergic inhibition plays a critical role in the pathogenesis. In the present study, we therefore examined the effects of selective GABA uptake inhibitors on severity of dystonia in dtsz hamsters. R(-)N-(4,4-di(3-methylthien-2-yl)-but-3-enyl) nipecotic acid hydrochloride (tiagabine, 5-20 mg/kg i.p.) and 1-[2-[[(diphenylmethylene) imino]oxy]ethyl]-1,2,5,6-tetrahydro-3-pyridinecarboxylic acid hydrochloride (NNC-711, 1-10 mg/kg i.p.) significantly reduced the severity of dystonia. These data suggest that GABA uptake inhibitors may provide novel therapeutic approaches for paroxysmal dyskinesias.     

Ongoing trials in HIV protease inhibitors

The development of antiretrovirals has led to a revolution in the care of patients infected with HIV. What was once a uniformly fatal syndrome has become a more treatable, chronic, infectious disease. Central to this revolution have been the protease inhibitors, a class of drugs with potent antiretroviral activity. The first member of this class was approved for use in 1995 and there are now five protease inhibitors approved by the US Food and Drug Administration (FDA): amprenavir, indinavir, nelfinavir, ritonavir and saquinavir. As a result of the magnitude of the HIV pandemic coupled with the clinically proven efficacy of protease inhibitors, there are currently hundreds of ongoing clinical trials with these agents. Trial designs include comparisons between the various licensed protease inhibitors, comparisons of protease inhibitors to other classes of potent antiretroviral drugs, investigations with new protease inhibitors, investigations of protease inhibitor-related toxicities and attempts at simplifying current dosing regimens.     

Fat distribution and HIV protease inhibitors

(1) Disturbing changes in body fat distribution started to be described in 1997 in HIV-infected patients treated with antiretroviral drugs, with fat accumulation at various levels of the trunk, and thinning of the limbs, buttocks and face. (2) The vast majority of cases occurred in patients on HIV protease inhibitors. (3) The long-term clinical consequences are unknown.     

Antileishmanial activity of HIV protease inhibitors

The proteasomes of some protozoa are possible targets for chemotherapy. Leishmaniasis is a major health problem in human immunodeficiency virus (HIV) co-infected subjects. Two HIV protease inhibitors (PI), indinavir and saquinavir, have been shown to block proteasome functions; we therefore investigated their effects on the growth of two Leishmania spp. (Leishmania major and Leishmania infantum). After 24 h of treatment, both drugs exhibited a dose-dependent antileishmanial activity, with 50% lethal dose (LD50) values of, respectively, 8.3 microM and 7 microM on L. major; minor activity was observed on L. infantum. These results add new in vitro insights into the wide-spectrum efficacy of PI and suggest studying their action on amastigote forms of leishmania within macrophages in order to validate their potential contribution against opportunistic infections in treated seropositive patients.     

HIV蛋白酶抑制剂的药代动力学相互作用

艾滋病的治疗是一个长期的过程,HIV蛋白酶抑制剂是此类病人最常选用的抗病毒药物。在治疗过程中,病人很可能患其它疾病,艾滋病自身也常伴随众多并发症,使得临床上不可避免的需要联用其它药物。由于HIV蛋白酶抑制剂对药物代谢酶和转运体有广泛的作用,因此探索HIV蛋白酶抑制剂的药物相互作用问题显得十分必要。本文重点从药代相互作用机制的角度综述了HIV蛋白酶抑制剂在临床上可能出现的药物相互作用方面的研究文献,包括HIV蛋白酶抑制剂与其它药物的相互作用以及蛋白酶抑制剂之间的相互作用及机制等,期望对于临床给药方案的设计和提高临床用药的安全性和有效性提供有价值的参考和借鉴。     

Brain delivery of HIV protease inhibitors

To overcome the problems of peptidomimetic drug delivery to the specific organs, the use of dihydropyridine <--> pyridinium chemical delivery systems to deliver peptides to the brain is considered in this work. An HIV protease inhibitor lead compound; KNI 279 was selected for the study. The N-alkylated dihydroisoquinoline derivatives of KNI-279 were synthesized and tested for their ability to be oxidized by brain homogenate and showed good results with reasonable half-life times specially for the N-alkoxycarbonyl-methyl derivative 8. The in-vivo distribution of compound 8 proved the brain delivery and locked in property of HIV PR inhibitors in the brain. All the prepared compounds (both quaternary and dihydro derivatives) showed between 51 and 86 % HIV PR inhibitory activity compared to the parent compound.     

Synthesis and biological evaluation of D-amino acid oxidase inhibitors

D-amino acid oxidase (DAAO) catalyzes the oxidation of D-amino acids including d-serine, a full agonist at the glycine site of the NMDA receptor. A series of benzo[ d]isoxazol-3-ol derivatives were synthesized and evaluated as DAAO inhibitors. Among them, 5-chloro-benzo[ d]isoxazol-3-ol (CBIO) potently inhibited DAAO with an IC50 in the submicromolar range. Oral administration of CBIO in conjunction with d-serine enhanced the plasma and brain levels of d-serine in rats compared to the oral administration of d-serine alone.     

HIV蛋白酶抑制剂研究进展

艾滋病 (acquiredimmunodeficiencysyndrome,AIDS)是由人免疫缺陷病毒(humanimmunodeficiencyvirus,HIV)感染导致人体免疫机能缺陷,而易于发生机会性感染和肿瘤的临床综合征 [1]。在过去的20多年里造成2 000多万人死亡,目前全世界艾滋病病毒感染者已达4 000万左右 [2]。自     

Synthesis of functionalized non-natural amino acid derivatives via amidoalkylation transformations

Synthetic routes have been developed for the preparation of functionalized amino acid derivatives in which the α-substituent at carbon 2 is either an aromatic or a heteroaromatic group. The α-substituent was introduced using an amidoalkylation reaction using boron trifluoride etherate and proceeded in moderate yield with excellent regioselectivity. This protocol permitted the employment of the acid sensitive heterocycles: pyrrole, benzofuran, and indole. The scope and limitations of this procedure have been evaluated.     

HIV蛋白酶抑制剂临床应用及评价

艾滋病（获得性免疫缺陷综合征,AIDS）危害人类健康，破坏家庭，威胁社会。2004年全世界艾滋病感染人数又创新高，中国目前的形势也不容乐观。HIV（human immunodeficiency virus,人免疫缺陷病毒）蛋白酶抑制剂能够有效抑制病毒复制，迅速成为治疗艾滋病的主要药物。本文通过查阅国内外近期关于HIV蛋白酶抑制剂的文献资料，对HIV蛋白酶抑制剂目前运用的现状和临床评价进行综述。     

Structure-based design of non-peptide HIV protease inhibitors

A number of structurally novel P2-ligands have been designed and synthesized. Incorporation of these ligands in the (R)-(hydroxyethyl)sulfonamide isostere provided a series of potent non-peptidyl HIV protease inhibitors.     

Determining and overcoming resistance to HIV protease inhibitors

HIV protease represents a major target for development of antiviral therapeutics. The introduction of HIV protease (PR) inhibitors (PIs) to clinical practice and the application of highly active antiretroviral therapy resulted in decreased mortality and prolonged life expectancy of HIV-positive patients. However, the high polymorphism of HIV leads to rapid selection of viral variants resistant towards the inhibitors. Such resistant PR variants have developed in HIV-positive patients after treatment with any of the eight PIs approved for clinical use. In this review we overview (i) the methods for the identification and assessment of viral resistance in HIV positive patients, and (ii) the approaches medicinal chemists take to overcome it. Rational antiviral therapy brings about the need for quantitative assessment of the level of drug resistance development in the course of the treatment. At present, two main approaches are taken: in genotypic assays the viral sequences are PCR amplified, sequenced and changes in the viral gene sequence known to be associated with reduced drug sensitivity are identified, while phenotypic assays test the ability of a virus to grow in the presence of a drug or combination of drugs. The advantages and drawbacks of these methods, as well as their relevance for the therapy are discussed. We also review the efforts to design second-generation PIs, capable of potently inhibiting multi-resistant HIV-1 PR species, using structure-assisted design of the compounds targeted to the active site, as well as alternative approaches with compounds binding to other domains of the PR molecule.     

Discovery of next generation inhibitors of HIV protease

Due to factors such as resistance and long-term side effects as well as dosing regimen-related adherence issues, HIV therapy is a constantly moving target. HIV-1 protease inhibitors had an immediate and dramatic impact on the outcome of HIV/AIDS when launched in late 1995, and the search for new and improved next generation molecules has been under way in many laboratories. At GlaxoSmithKline (GSK) and Vertex Pharmaceuticals, this effort focused on two key issues, patient compliance and viral resistance. Using a water-solubilizing prodrug approach, the pill-burden in delivering our protease inhibitor, amprenavir, was dramatically decreased. By eliminating the large amounts of excipients necessary for the original soft-gel formulation, fosamprenavir (Lexiva/Telzir) delivers the clinically efficacious dose of amprenavir with two compact tablets per dose, compared to eight gel capsules. Our efforts to overcome viral resistance to 1(st) generation protease inhibitors by further elaborating the SAR of the amprenavir and related scaffolds, led to successive and dramatic improvements in wild-type antiviral potencies, and ultimately to the discovery of "ultra-potent" molecules with very favorable overall resistance profiles. The selection of GW640385 (brecanvir--USAN approved only) as a clinical candidate and its progression into current phase 2 dose ranging studies represents the culmination of our effort toward next generation protease inhibitors.