New helicase-primase inhibitors as drug candidates for the treatment of herpes simplex disease

The vast majority of the world population is infected with at least one member of the human herpesvirus family. Herpes simplex virus (HSV) infections are the cause of cold sores and genital herpes as well as life-threatening or sight-impairing disease mainly in immunocompromized patients, pregnant women and newborns. Since the milestone development in the late 1970s of acyclovir (Zovirax), a nucleosidic inhibitor of the herpes DNA polymerase, no new non-nucleosidic anti-herpes drugs have been introduced. Here we report new inhibitors of the HSV helicase-primase with potent in vitro anti-herpes activity, a novel mechanism of action, a low resistance rate and superior efficacy against HSV in animal models. BAY 57-1293 (N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide), a well-tolerated member of this class of compounds, significantly reduces time to healing, prevents rebound of disease after cessation of treatment and, most importantly, reduces frequency and severity of recurrent disease. Thus, this class of drugs has significant potential for the treatment of HSV disease in humans, including those resistant to current medications.     

Nasal vaccination with beta-amyloid peptide for the treatment of Alzheimer's disease.

Alzheimer's disease (AD) is a severe neurodegenerative disease for which there is currently no effective prevention or treatment. The prediction that the number of U.S. patients with AD will triple to approximately 14 million over the next 50 years underscores the urgent need to explore novel therapeutic strategies for AD. The beta-amyloid protein (Abeta) accumulation and accompanying inflammation appear to play key roles in initiating the neuronal degeneration that underlies the signs and symptoms of AD. Interventions geared toward reducing Abeta accumulation and inflammatory responses should delay or prevent the onset of the clinical disease. Recently, several research groups, including ours, have shown that vaccination with Abeta results in a significant lowering of the Abeta burden in the brains of APP transgenic mice and, in some studies, improvement in their cognitive deficits. Our study described a novel approach, namely mucosal (intranasal) Abeta vaccination. Precisely how Abeta vaccination chronically lowers Abeta levels and reduces Abeta-associated pathology remains unclear. Here, we provide an overview of these studies, with particular emphasis on our work with intranasal Abeta vaccination. Examples of other intranasal vaccines and mucosal adjuvants are presented. Taken together, these data have implications for the future development of an intranasal Abeta vaccine for humans.     

Synthesis and structure-activity relationship study of multi-target triazine derivatives as innovative candidates for treatment of Alzheimer's disease

The complex pathogenesis of Alzheimer’s disease (AD) requires using multi-target ligands (MTLs) for disease management. We synthesized, characterized and evaluated a series of novel triazine analogues as MTLs for AD. The biological screening results indicated that most of our compounds displayed potent inhibitory activities against β-site APP-cleaving enzyme 1 (BACE1) using a FRET-based assay. Compounds 6c and 6m were found to possess significant BACE1 inhibitory properties with IC₅₀ values of 0.91 (±0.25) µM and 0.69 (±0.20) µM, respectively. DPPH radical scavenging activity evaluation showed that compounds with hydroxyl and pyrrole moieties had antioxidant effects. Docking evaluations provided insight into enzyme inhibitory interactions of novel synthesized compounds with the BACE1 active site involving a critical role for Gln73 and/or Phe108 alongside of Asp32. Metal chelation tests confirmed that compound 6m is a chelator for Fe²⁺, Fe³⁺, Zn²⁺, Cu²⁺. Moreover 6m as the most potent BACE1 inhibitor did not show any toxicity against PC12 neuronal cells. These findings demonstrate the high potential of triazine scaffolds in the design of MTLs for treatment of AD.     

Abeta-immunotherapy for Alzheimer's disease using mannan-amyloid-Beta peptide immunoconjugates

In Alzheimer's disease (AD) the accumulation of pathological forms of the beta-amyloid (Abeta) peptide are believed to be causal factors in the neurodegeneration that results in the loss of cognitive function in patients. Anti-Abeta antibodies have been shown to reduce Abeta levels in transgenic mouse models of AD and in AN-1792 clinical trial on AD patients; however, the clinical trial was halted when some patients developed meningoencephalitis. Theories on the cause of the adverse events include proinflammatory "primed patients," a Th1-inducing adjuvant, and Abeta autoreactive T cells. New immunotherapy approaches are being developed to eliminate these putative risk factors. Mannan, which is recognized by pattern recognition receptors of the innate immune system, can be utilized as a molecular adjuvant to promote a Th2-mediated immune response to conjugated B cell epitopes. The N-terminus of Abeta was conjugated to mannan, and used to immunize mice with low concentrations of immunoconjugate, without a conventional adjuvant. Mannan induced a significant and highly polarized toward Th2 phenotype anti-Abeta antibody response not only in BALB/c, but also in B6SJL F1 mice. New preclinical trials in AD mouse models may help to develop novel immunogen-adjuvant configurations with the potential to avoid the adverse immune response that occurred in the first clinical trial.     

Retinoids for treatment of Alzheimer's disease

Retinoids are Vitamin A derivatives involved in cellular regulatory processes including cell differentiation, neurite outgrowth and defense against oxidative stress. Retinoids may also influence Amyloid beta processing upregulation of alpha secretase via ADAM10. Vitamin A and other retinoids also directly inhibit formation of Amyloid fibrils in vivo. These properties of retinoids are relevant to theories of Alzheimer's disease pathogenesis. Retinoids are already used in treatment of acne vulgaris, psoriasis, neuroblastoma and acute promyelocytic leukemia. Clinical studies involving in cognitively impaired older adults with Alzheimer's disease are beginning with a variety of retinoids. These studies need to address safety issues of retinoids in older populations, and hold hope for demonstrating efficacy in translating these basic mechanisms to treatment of a widespread dementing illness.     

Bioinformatic analysis of the SPs and NFTs proteomes unravel putative biomarker candidates for Alzheimer's disease

Aging is the main risk factor for the appearance of age-related neurodegenerative diseases, including Alzheimer's disease (AD). AD is the most common form of dementia, characterized by the presence of senile plaques (SPs) and neurofibrillary tangles (NFTs), the main histopathological hallmarks in AD brains. The core of these deposits are predominantly amyloid fibrils in SPs and hyperphosphorylated Tau protein in NFTs, but other molecular components can be found associated with these pathological lesions. Herein, an extensive literature review was carried out to obtain the SPs and NFTs proteomes, followed by a bioinformatic analysis and further putative biomarker validation. For SPs, 857 proteins were recovered, and, for NFTs, 627 proteins of which 375 occur in both groups and represent the common proteome. Gene Ontology (GO) enrichment analysis permitted the identification of biological processes and the molecular functions most associated with these lesions. Analysis of the SPs and NFTs common proteins unraveled pathways and molecular targets linking both histopathological events. Further, validation of a putative phosphotarget arising from the in silico analysis was performed in serum-derived extracellular vesicles from AD patients. This bioinformatic approach contributed to the identification of putative molecular targets, valuable for AD diagnostic or therapeutic intervention.     

Biomarkers in Alzheimer's disease drug development

Biomarkers may be of great value in Alzheimer's disease drug development to select the most optimal drug candidates for large and expensive phase 3 clinical trials. Biomarkers will also be important to provide evidence that a drug affects the underlying pathophysiology of the disease, which, together with a beneficial effect on the clinical course, will be essential for labeling the drug as having a disease-modifying effect.     

Novel bisbenzamidines as potential drug candidates for the treatment of Pneumocystis carinii pneumonia

A series of pentamidine congeners has been synthesized and screened for their in vitro activity against Pneumocystis carinii. Among the tested compounds, bisbenzamidines linked by a flexible pentanediamide or hexanediamide chain (7 and 9) emerged as exceptionally potent agents that were more effective and less toxic than pentamidine in the assays described in this study.     

Memapsin 2, a drug target for Alzheimer's disease

Mempasin 2, a beta-secretase, is the membrane-anchored aspartic protease that initiates the cleavage of amyloid precursor protein leading to the production of beta-amyloid and the onset of Alzheimer's disease. Thus memapsin 2 is a major therapeutic target for the development of inhibitor drugs for the disease. Many biochemical tools, such as the specificity and crystal structure, have been established and have led to the design of potent and relatively small transition-state inhibitors. Although developing a clinically viable mempasin 2 inhibitor remains challenging, progress to date renders hope that memapsin 2 inhibitors may ultimately be useful for therapeutic reduction of beta-amyloid.     

β淀粉样蛋白的分泌酶与阿尔采末病的治疗

β淀粉样蛋白(Aβ)级联反应在阿尔采末病(AD)发病过程中起主要作用,Aβ由分泌酶中的β和γ分泌酶水解β淀粉样蛋白前体蛋白(APP)而来。本文综述了参与APP水解的三种分泌酶(α、β和γ)的发现、研究进展及其在调节β淀粉样蛋白过程中的作用。选择性地激活α分泌薄或抑制β和γ分泌酶格减少Aβ产生,为AD治疗提供新的研究思路,以分泌酶为靶点可能成为治疗AD的理想途径。     

Secretases as targets for the treatment of Alzheimer's disease

Alzheimer's disease (AD) is the major cause of dementia in most developed countries. Treatment to modify this disease is currently unavailable, but needed urgently. The amyloid-cascade hypothesis proposes that amyloid beta-peptide (Abeta), found in the plaques characteristic of AD, plays an early, critical role in the disease process. It follows that preventing the generation of Abeta could be therapeutically useful in all cases of AD. Inhibition of the secretases that produce Abeta from a large precursor protein is the main approach to achieve this goal.     

Structural studies of Alzheimer's disease Abeta peptide oligomers

Amyloid beta peptide is recognized as the main constituent of the extracellular amyloid plaques, the major neuropathological hallmark of Alzheimer's disease. Abeta is a small peptide constitutively expressed in normal cells, not toxic in the monomeric form but aggregated Abeta is assumed to be the main if not the only factor causing Alzheimer's disease. Interestingly, the new reports suggest neurotoxicity of soluble Abeta oligomers rather than amyloid fibrils. Because of the fact that fibrils were thought to be the main toxic species in AD, early structural studies focused on fibrils themselves and Abeta monomers, as their building blocks while there is practically no data on oligomer structure and mechanism of neurotoxicity. Using a model peptide spanning residues 10–30 of Abeta, obtained by overexpression in bacteria, we have employed mass spectrometry of noncovalent complexes and disulfide rearrangement assay to gain new insight into structure and dynamics of a prenucleation step of Abeta peptide oligomerisation.     

The redox chemistry of the Alzheimer's disease amyloid beta peptide

There is a growing body of evidence to support a role for oxidative stress in Alzheimer's disease (AD), with increased levels of lipid peroxidation, DNA and protein oxidation products (HNE, 8-HO-guanidine and protein carbonyls respectively) in AD brains. The brain is a highly oxidative organ consuming 20% of the body's oxygen despite accounting for only 2% of the total body weight. With normal ageing the brain accumulates metals ions such iron (Fe), zinc (Zn) and copper (Cu). Consequently the brain is abundant in antioxidants to control and prevent the detrimental formation of reactive oxygen species (ROS) generated via Fenton chemistry involving redox active metal ion reduction and activation of molecular oxygen. In AD there is an over accumulation of the Amyloid beta peptide (Abeta), this is the result of either an elevated generation from amyloid precursor protein (APP) or inefficient clearance of Abeta from the brain. Abeta can efficiently generate reactive oxygen species in the presence of the transition metals copper and iron in vitro. Under oxidative conditions Abeta will form stable dityrosine cross-linked dimers which are generated from free radical attack on the tyrosine residue at position 10. There are elevated levels of urea and SDS resistant stable linked Abeta oligomers as well as dityrosine cross-linked peptides and proteins in AD brain. Since soluble Abeta levels correlate best with the degree of degeneration [C.A. McLean, R.A. Cherny, F.W. Fraser, S.J. Fuller, M.J. Smith, K. Beyreuther, A.I. Bush, C.L. Masters, Soluble pool of Abeta amyloid as a determinant of severity of neurodegeneration in Alzheimer's disease, Ann. Neurol. 46 (1999) 860-866] we suggest that the toxic Abeta species corresponds to a soluble dityrosine cross-linked oligomer. Current therapeutic strategies using metal chelators such as clioquinol and desferrioxamine have had some success in altering the progression of AD symptoms. Similarly, natural antioxidants curcumin and ginkgo extract have modest but positive effects in slowing AD development. Therefore, drugs that target the oxidative pathways in AD could have genuine therapeutic efficacy.     

Selection of RNA aptamers to the Alzheimer's disease amyloid peptide

Alzheimer's disease is correlated with the deposition of amyloid peptides in the brain of the patients. The amyloid is thus a major target in the search for novel diagnostic and therapeutic approaches. The present work employs in vitro selection to develop new tools for the study of the Alzheimer's disease. The selection strategy enables the design of specific nucleic acids (aptamers) against virtually any target molecule. High-affinity RNA aptamers against the betaA4(1-40) were isolated from a combinatorial library of approximately 10(15) different molecules. The apparent dissociation constants K(d) of these aptamers are 29-48 nM. The binding of the RNA to the amyloid fibrils was confirmed by electron microscopy. The chemical synthesis of these nucleic acids enables tailor-made modifications. By introduction of specific reporter groups these RNAs can become suitable tools for analytical and diagnostic purposes. Thus, this study may introduce a new approach for diagnosis of the Alzheimer's disease.     

Alzheimer's disease, amyloid peptide and synaptic dysfunction

Alzheimer's disease (AD) is the first cause of dementia that leads to insidious and progressive loss of memory and cognitive functions. In the early stages of AD, there is a strong correlation between memory impairment and cortical levels of soluble amyloid-β peptide oligomers (Aβ). It has become clear that Aβ disrupt glutamatergic synaptic function, which in turn may lead to the characteristic cognitive deficits. Conversely, experiments in rodents have conforted the notion that Aβo impairs synaptic transmission and plasticity, and that mouse models with increased production of these oligomers display cognitive impairment. Many studies have attempted to determine the mechanisms by which Aβo disrupt synaptic plasticity and mediate their detrimental effect, but the actual pathways are still poorly understood. Here we review this thriving area of research which aims at understanding the mechanisms of synaptic dysfunction in the early phase of AD, and its consequences on the activity of neural circuits.     

A novel neurotrophic drug for cognitive enhancement and Alzheimer's disease

Currently, the major drug discovery paradigm for neurodegenerative diseases is based upon high affinity ligands for single disease-specific targets. For Alzheimer''s disease (AD), the focus is the amyloid beta peptide (Aß) that mediates familial Alzheimer''s disease pathology. However, given that age is the greatest risk factor for AD, we explored an alternative drug discovery scheme that is based upon efficacy in multiple cell culture models of age-associated pathologies rather than exclusively amyloid metabolism. Using this approach, we identified an exceptionally potent, orally active, neurotrophic molecule that facilitates memory in normal rodents, and prevents the loss of synaptic proteins and cognitive decline in a transgenic AD mouse model.     

胰高血糖素样肽1:阿尔茨海默病治疗新策略

2型糖尿病(type2diabetes mellitus,T2DM)与阿尔茨海默病(Alzheimer’s disease,AD)的病理生理过程具有密切的相关性。人们正在逐步深入研究治疗T2DM的最新药物——胰高血糖素样肽1(glucagon-likepe ptide1,GLP-1)的神经保护作用,并大胆地提出了利用GLP-1治疗AD的设想。本文对T2DM与AD的发病相关性、GLP-1的合成与分泌、GLP-1受体的中枢分布及其生理效应,特别是GLP-1与AD治疗策略相关的研究进展作一综述。     

Presenilins as therapeutic targets for the treatment of Alzheimer's disease

Studies demonstrating that accumulation and aggregation of the amyloid beta protein (Abeta) within the brain is likely to cause Alzheimer's disease (AD) have provided the rationale for therapeutic strategies aimed at influencing Abeta production, aggregation and clearance. gamma-secretase catalyzes the final cleavage that releases the Abeta from its precursor; therefore, it is a potential therapeutic target for the treatment of AD. Recent data show that the polytopic membrane proteins presenilin 1 and presenilin 2 are either catalytic components or essential co-factors of a membrane-bound proteolytic complex that possesses gamma-secretase activity. Although recent findings demonstrating that gamma-secretase inhibitors bind directly to presenilins (PSs) further support a catalytic role for PSs in gamma-secretase cleavage, additional studies are still needed to clarify the role of PSs in gamma-secretase cleavage and the use of targeting PSs to reduce Abeta production.