Fusion/entry inhibitors as therapies for HIV

A combination of three or more antiretroviral drugs, commonly termed 'highly active antiretroviral therapy' (HAART), has become the standard-of-care treatment for HIV-related disease in the developed world. Since its initiation in the mid 1990s, HAART has led to substantial reductions in both mortality and morbidity. There are, however, significant problems associated with existing therapies including high pill burdens and serious side effects in many patients, as well as the emergence and transmission of drug-resistant HIV variants. There is, therefore, a need for new medicines to treat HIV infections, both from the existing drug classes and, perhaps more importantly, a need for medicines that act against the virus in entirely new ways. In recent years, much has been learned about how HIV enters its target cells and this work has led to the identification of compounds that potently inhibit the individual steps of viral entry. The status of current research focussed on preventing HIV entry is described below.     

Antiretroviral activity of semisynthetic derivatives of glycopeptide antibiotics

A variety of semisynthetic derivatives of natural antibacterial glycopeptide antibiotics such as vancomycin, eremomycin, ristocetin A, teicoplanin A(2)-2, DA-40926, their aglycons, and also the products of their partial degradation with a destroyed or modified peptide core show marked anti-retroviral activity in cell culture. In particular, aglycon antibiotic derivatives containing various substituents of a preferably hydrophobic nature displayed activity against human immunodeficiency virus type 1 (HIV-1), HIV-2, and Moloney murine sarcoma virus at a 50% inhibitory concentration in the lower micromolar (1-5 microM) concentration range while not being cytostatic against human lymphocytic cells at 250 microM or higher. The mode of anti-HIV action of the antibiotic aglycon derivatives could be ascribed to inhibition of the viral entry process.     

Role of the glycopeptide framework in the antibacterial activity of hydrophobic derivatives of glycopeptide antibiotics

The antibacterial properties of glycopeptide antibiotics are based on their interaction with the d-Ala-d-Ala containing pentapeptide of bacterial peptidoglycan. The hydrophobic amides of vancomycin (1), teicoplanin (2), teicoplanin aglycon (3), and eremomycin (4) were compared with similar amides of minimally or low active des-(N-methyl-d-leucyl)eremomycin (5), eremomycin aglycon (6), des-(N-methyl-d-leucyl)eremomycin aglycon (7), and a teicoplanin degradation product TB-TPA (8). All hydrophobic amides of 1, 3, 4, and 6 were almost equally active against glycopeptide-resistant enterococci (GRE) [minimum inhibitory concentrations (MIC) 相似文献   

HIV entry inhibitors in clinical development

Despite recent advances, present therapies for human immunodeficiency virus type 1 (HIV-1) infection are limited by their failure to eradicate HIV-1, by the emergence of multidrug-resistant variants and by significant toxicities. Current therapies collectively target two viral enzymes involved in intracellular viral replication processes, and there is an urgent need for new treatment modalities. HIV-1 entry is a multistep process that comprises viral attachment, co-receptor interactions and fusion. This cascade of events offers opportunities for therapeutic intervention, and clinical proof-of-principle has been obtained for inhibitors of each step. These agents are referred to broadly as entry inhibitors.     

Novel beta-lactam antibiotics derivatives: their new applications as gene reporters, antitumor prodrugs and enzyme inhibitors

Since the antibiotic properties of penicillin were first noticed in the beginning of last century, beta-lactam based antibiotics have been well developed as miracle drugs for the therapy of bacterial infectious diseases in clinics. Recently, these "old" antibiotics and their relevant derivatives have also found new applications as gene reporters, anti-cancer prodrugs and enzyme inhibitors. In this review, we will introduce the latest developments in the study of these new applications based on literatures reported over the last decade. The first section covers the recent developments of beta-lactam antibiotics as drugs against bacteria, the second section briefly discusses the occurrence of bacterial resistance and mechanistic studies of beta-lactam resistance in bacteria, the third section presents the current development of fluorogenic cephalosporin based beta-lactam probes for real-time imaging of gene expression, and the fourth section describes relevant studies on beta-lactam based substrates as anti-tumor prodrugs. Beta-lactam substrates as protease inhibitors will be also described in the fifth section. The final section summarizes future perspectives for beta-lactam antibiotic derivatives as scaffolds in the fields of molecular imaging, drug delivery and enzymatic assays.     

人类免疫缺陷病毒进入抑制剂的临床开发与应用

耐药性是目前用抗病毒药物治疗获得性免疫缺陷综合征(艾滋病,AIDS)的主要问题。HIV进入抑制剂可以阻断HIV病毒进入人体细胞,具有新的作用机制,对其开发是目前解决耐药性问题的主要方向之一。目前国内已有多家单位在进行HIV进入抑制剂研究,有些即将进入临床试验阶段。本文结合我们自身的研究工作,着重综述了HIV进入抑制剂在预防与治疗艾滋病中的应用研究情况,特别讨论了其临床试验的目的、设计方案,以及进入抑制剂与目前药物联合使用的思路。     

N-甲酰羟胺类肽去甲酰酶抑制剂的合成及抗菌活性

目的 设计合成N-甲酰羟胺类肽去甲酰酶抑制剂,初步评价其体外抗菌活性.方法 以丙二酸二乙酯为起始原料,经多步反应合成目标化合物;采用对倍稀释法,测定目标化合物对金葡菌、表葡菌以及耐甲氧西林金葡菌、表葡菌的抑菌活性.结果与结论 合成了14个未见文献报道的目标化合物,其结构经1H-NMR、MS确证.体外试验表明:目标化合物均表现出一定的抗菌活性.     

HIV进入宿主细胞的分子机制及相关药物研究进展

艾滋病(AIDS)是由人类免疫缺陷病毒(HIV)引起的恶性传染病，HIV进入宿主细胞环节涉及病毒表面糖蛋白(gp120和gp41)与细胞表面受体蛋白(CD4，CCR5和CXCR4等)的相互作用。现就HIV进入细胞的分子生物学机制以及目前针对病毒吸附与穿入设计的新型抗AIDS药物作一综述。     

Hydroxamic acid derivatives as potent peptide deformylase inhibitors and antibacterial agents

Low-molecular-weight beta-sulfonyl- and beta-sulfinylhydroxamic acid derivatives have been synthesized and found to be potent inhibitors of Escherichia coli peptide deformylase (PDF). Most of the compounds synthesized and tested displayed antibacterial activities that cover several pathogens found in respiratory tract infections, including Chlamydia pneumoniae, Mycoplasma pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis. The potential of these compounds as antibacterial agents is discussed with respect to selectivity, intracellular concentrations in bacteria, and potential for resistance development.     

HIV entry inhibitors:progress in development and application

This review discusses recent progress in the development of anti-HIV agents, with emphasis on small molecule HIV-1 entry inhibitors.  The entry inhibitors primarily target HIV-1 envelope glycoproteins or the cellular receptors, CD4 and chemokine receptors.  Two of the entry inhibitors, enfuvirtide and maraviroc, have been approved by the US FDA for AIDS therapy.  The drug resistance associated with some of the entry inhibitors will also be discussed.     

Heteroaryl butyric acids and their derivatives as inhibitors of matrix metalloproteinases

This patent application is one of several applications from the Warner-Lambert company describing small molecule, non-peptide inhibitors of matrix metalloproteinases (MMPs). The MMPs are a class of over 20 zinc-binding enzymes comprised of collagenases, stromelysins, gelatinases and membrane type- (MT-) MMPs. Elevated levels of these enzymes, with their ability to break down the extracellular matrix and basement membrane, have been implicated in the aetiology of a wide variety of disease states including osteoarthritis, rheumatoid arthritis, cancer, wound healing, atherosclerosis, heart failure, multiple sclerosis and periodontal disease. The compounds claimed in this application are members of a growing list of non-peptide, carboxylic acid based MMP inhibitors which potentially offer increased bioavailability relative to the related hydroxamates. One of the compounds exemplified is a potent inhibitor of MMP-2, with an in vitro profile comparable to Bayer’s clinical candidate, BAY 12-9566.     

Glycopeptide antibiotics and their novel semi-synthetic derivatives

Glycopeptide antibiotics, vancomycin and teicoplanin, inhibit cell wall synthesis in Gram-positive bacteria by interacting with peptidoglycan D-Ala-D-Ala peptide stem termini of the pentapeptide side chains of the peptidoglycan precursors. In glycopeptide-resistant bacteria, multiresistance poses major therapeutic problems. New potent antibacterial agents are needed to combat these resistance problems, resulting in the explosion of novel glycopeptides in recent years. The glycosylation patterns of glycopeptides and the chemical modifications of the glycosyl moieties greatly influence their antibiotic activity, and certain combinations have resulted in highly active new compounds. Considerable efforts have been made to produce semisynthetic glycopeptides with improved pharmacokinetic and pharmacodynamic properties and activity towards resistant strains. This review provides an overview of the chemistry, the antimicrobial activity, the pharmacokinetics and the toxicology of teicoplanin and other glycopeptide antibiotic derivatives.