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Exploring Modifications of an HIV-1 Capsid Inhibitor: Design, Synthesis, and Mechanism of Action. 探索修饰HIV-1衣壳抑制剂:设计、合成和作用机制。
Pub Date : 2018-01-01 Epub Date: 2018-08-13
Jimmy P Xu, Ashwanth C Francis, Megan E Meuser, Marie Mankowski, Roger G Ptak, Adel A Rashad, Gregory B Melikyan, Simon Cocklin

Recent efforts by both academic and pharmaceutical researchers have focused on the HIV-1 capsid (CA) protein as a new therapeutic target. An interprotomer pocket within the hexamer configuration of the CA, which is also a binding site for key host dependency factors, is the target of the most widely studied CA inhibitor compound PF-3450074 (PF-74). Despite its popularity, PF-74 suffers from properties that limit its usefulness as a lead, most notably it's extremely poor metabolic stability. To minimize unfavorable qualities, we investigated bioisosteric modification of the PF-74 scaffold as a first step in redeveloping this compound. Using a field-based bioisostere identification method, coupled with biochemical and biological assessment, we have created four new compounds that inhibit HIV-1 infection and that bind to the assembled CA hexamer. Detailed mechanism of action studies indicates that the modifications alter the manner in which these new compounds affect HIV-1 capsid core stability, as compared to the parental compound. Further investigations are underway to redevelop these compounds to optimize potency and drug-like characteristics and to deeply define the mechanism of action.

近年来,学术界和制药研究人员都将HIV-1衣壳蛋白(CA)作为一种新的治疗靶点。在CA的六聚体结构中,有一个互原体口袋,它也是关键宿主依赖因子的结合位点,是研究最广泛的CA抑制剂化合物PF-3450074 (PF-74)的靶标。尽管它很受欢迎,但PF-74的特性限制了它作为铅的用途,最明显的是它的代谢稳定性非常差。为了尽量减少不利的品质,我们研究了PF-74支架的生物等构修饰,作为重新开发该化合物的第一步。利用基于现场的生物同位体鉴定方法,结合生化和生物学评估,我们创造了四种抑制HIV-1感染的新化合物,并与组装的CA六聚体结合。详细的作用机制研究表明,与亲本化合物相比,这些修饰改变了这些新化合物影响HIV-1衣壳核心稳定性的方式。进一步的研究正在进行中,以重新开发这些化合物,以优化效力和药物样特性,并深入确定作用机制。
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引用次数: 0
Sex Differences in the Motivational Contrast between Sucrose and Cocaine in Rats. 蔗糖和可卡因对大鼠动机对比的性别差异。
Pub Date : 2017-01-01 Epub Date: 2017-03-28
Udita Datta, Mariangela Martini, Wen Lin Sun

There are sex differences in the vulnerability to cocaine abuse and addiction. Understanding the differences is critical for developing the sex-tailored prevention and treatment strategies. Cocaine addiction is characterized by the pathological motivation for cocaine accompanied by the diminished motivation for natural rewards. Thus, the motivational impact of cocaine relative to natural rewards likely determines the attractiveness of cocaine and likely plays a role in the vulnerability to cocaine abuse and addiction. This study aimed to determine whether the relative magnitudes or contrast of the motivational impact between cocaine and sucrose is different between sexes. To this end, cocaine-naïve out bred Wistar rats were trained to self-administer sucrose pellets and the motivation for different amounts of sucrose was then determined as the breakpoints under the progressive-ratio schedule of reinforcement. Following the sucrose tests, the same rats were trained to self-administer cocaine and the motivation for different doses of cocaine was similarly measured. For the female rats, the motivation was also measured during the diestrus and proestrus/estrus, respectively, to determine the impact of the estrous cycle on the motivational effects of cocaine and sucrose. The differences between the breakpoints of cocaine and sucrose were significantly larger in the males. The enhanced motivational contrast may contribute to the increased vulnerability to recreational cocaine abuse and addiction in the males.

对可卡因滥用和成瘾的易感性存在性别差异。了解这些差异对于制定针对不同性别的预防和治疗策略至关重要。可卡因成瘾的特点是可卡因的病理动机伴随着自然奖励动机的减弱。因此,相对于自然奖励而言,可卡因的动机影响可能决定了可卡因的吸引力,并可能在可卡因滥用和成瘾的脆弱性中发挥作用。本研究旨在确定可卡因和蔗糖对动机影响的相对大小或对比是否在性别之间有所不同。为此,我们训练cocaine-naïve外种Wistar大鼠自我给药蔗糖颗粒,并确定不同蔗糖量的动机作为渐进-比例强化计划下的断点。在蔗糖测试之后,同样的大鼠被训练自我服用可卡因,并且对不同剂量可卡因的动机进行了类似的测量。在雌性大鼠的发情期和发情前/发情期也分别测量其动机,以确定发情周期对可卡因和蔗糖的动机效应的影响。在男性中,可卡因和蔗糖的断点差异明显更大。动机对比的增强可能导致男性娱乐性可卡因滥用和成瘾的易感性增加。
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引用次数: 0
Epigenetic Basis of Clozapine Action. 氯氮平作用的表观遗传学基础。
Pub Date : 2017-01-01 Epub Date: 2017-06-29
Guidotti Alessandro, Dong Erbo, Dennis R Grayson
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引用次数: 0
Tissue Plasminogen Activator: Side Effects and Signaling. 组织纤溶酶原激活剂:副作用和信号传导。
Pub Date : 2014-09-25
Ling Lin, Kebin Hu
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引用次数: 0
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Journal of drug design and research
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