Optimization of 1,3-disubstituted urea-based inhibitors of Zika virus infection

Zika virus (ZIKV) has become a public health concern worldwide due to its association with congenital abnormalities and neurological diseases. To date, no effective vaccines or antiviral drugs have been approved for the treatment of ZIKV infection, and new inexpensive therapeutic options are urgently needed. In this study, we have used an in vitro plaque assay to assess an antiviral activity of the second generation of anti-ZIKV compounds, based on 1,3-disubstituted (thio)urea scaffold. Several compounds in the library were found to possess excellent activity against Zika virus with IC₅₀ values <200 pM. The most active analog, A5 exhibited an exceptional IC₅₀ = 85.1 ± 1.7 pM. Further analysis delineated structural requirements necessary for potent antiviral effects of this class of compounds. Collectively, our findings suggest that 1,3-disubstituted (thio)urea derivatives are excellent preclinical candidates for the development of anti-ZIKV therapeutics.     

Zika virus and Zika fever

An emerging mosquito-borne arbovirus named Zika virus (ZIKV), of the family Flaviviridae and genus Flavivirus, is becoming a global health threat. ZIKV infection was long neglected due to its sporadic nature and mild symptoms. However, recently, with its rapid spread from Asia to the Americas, affecting more than 30 countries, accumulating evidences have demonstrated a close association between infant microcephaly and Zika infection in pregnant women. Here, we reviewed the virological, epidemiological, and clinical essentials of ZIKV infection.

Open image in new window

     

Identification of novel small-molecule inhibitors of Zika virus infection

The recent re-emergence of Zika virus (ZIKV), a member of the Flaviviridae family, has become a global emergency and a serious public health threat worldwide. ZIKV infection causes severe neuroimmunopathology and is particularly harmful to the developing fetuses of infected pregnant women causing various developmental abnormalities. Currently, there are no effective methods of preventing or treating ZIKV infection, and new treatment options are urgently needed. Therefore, we have used an in vitro plaque assay to screen a limited proprietary library of small organic compounds and identified highly bioactive leads, with the most active analogs showing activity in low picomolar range. Identified “hits” possess certain common structural features that can be used in the design of the next generation(s) of ZIKV inhibitors. Collectively, our findings suggest that identified compounds represent excellent template(s) for the development of inexpensive and orally available anti-Zika drugs.     

寨卡疫苗研究进展

寨卡病毒系由伊蚊传播的黄病毒,超过20亿人在其流行区域生活。近几年,在中南美洲乃至世界范围内爆发的寨卡疫情已对全球公共卫生事业构成严重威胁。已有研究证实寨卡病毒感染为格林巴利综合征的病因之一;孕妇感染寨卡病毒后,可造成新生儿小头症。早日研制出安全有效的寨卡疫苗之重要性不言而喻。全球率先报道的寨卡疫苗为一款DNA疫苗,其在设计、制备和生产方面均较其他类型疫苗更加简易,且可避免可复制型疫苗因毒力回复而造成对孕妇和胎儿的健康威胁,在寨卡疫苗的研究中具有显著优势。其他传统类型疫苗和基于抗体的新型疫苗等均有研究机构开展研究,并已取得阶段性进展,本文将扼要综述寨卡疫苗的研究现状与进展。     

Zika病毒与Zika病毒病

Zika病毒(Zika virus,ZIKV)是一种新现虫媒病毒,属于黄病毒科黄病毒属。其感染后临床表现为轻症发热,因病重住院者罕见。流行病学数据显示Zika病毒病的流行与自身免疫性神经性疾病格林-巴利综合征及先天性小头畸形有关,引起了专家和公众的关注,但具体机制有待深入研究。     

Zika infection and the development of neurological defects

Starting with the outbreak in Brazil, Zika virus (ZIKV) infection has been correlated with severe syndromes such as congenital Zika syndrome and Guillain‐Barré syndrome. Here, we review the status of Zika virus pathogenesis in the central nervous system (CNS). One of the main concerns about ZIKV exposure during pregnancy is abnormal brain development, which results in microcephaly in newborns. Recent advances in in vitro research show that ZIKV can infect and obliterate cells from the CNS, such as progenitors, neurons, and glial cells. Neural progenitor cells seem to be the main target of the virus, with infection leading to less cell migration, neurogenesis impairment, cell death and, consequently, microcephaly in newborns. The downsizing of the brain can be directly associated with defective development of the cortical layer. In addition, in vivo investigations in mice reveal that ZIKV can cross the placenta and migrate to fetuses, but with a significant neurotropism, which results in brain damage for the pups. Another finding shows that hydrocephaly is an additional consequence of ZIKV infection, being detected during embryonic and fetal development in mouse, as well as after birth in humans. In spite of the advances in ZIKV research in the last year, the mechanisms underlying ZIKV infection in the CNS require further investigation particularly as there are currently no treatments or vaccines against ZIKV infection.     

The fertility-inhibiting effect of mosquitoes: Socio-economic differences in response to the Zika crisis in Colombia

We estimated the impact of the Zika virus outbreak on birth rates and demand for health care services in Colombia. Our analysis exploits the variation in the level of natural protection against mosquito-transmitted diseases across the country. This characteristic induced exogenous variation in Zika incidence, which allows us to construct a control group of municipalities with similar historical fertility trends but with differential exposure to the Zika crisis. We implemented a difference-in-differences model after matching, as well as synthetic control. We found a decrease in birth rates of approx. 10% in the last two quarters of 2019. The impact of the virus was similar irrespective of the women’s education level, and we found no discernible impact on teenage pregnancy.     

Oviposition of Aedes aegypti Linnaeus, 1762 and Aedes albopictus Skuse, 1894 (Diptera: Culicidae) under laboratory and field conditions using ovitraps associated to different control agents,Manaus, Amazonas,Brazil

The aim of this study was to analyze the effectiveness of different control agents of Aedes aegypti and Aedes albopictus associated with ovitraps under laboratory and field conditions. Five treatments were used: grass infusion + Bacillus thuringiensis israelensis (gI + Bti), grass infusion + Saccharopolyspora spinosa (gI + Ss), grass infusion + Pyriproxyfen (gI + P), distilled water + Toxorhynchites haemorrhoidalis (dW + Th), and grass infusion (gI) (control). The highest mean number of eggs of both species were obtained with grass infusion in the laboratory. Among control agents, the lowest mean of A. aegypti eggs occurred with gI + Ss and the lowest mean of A. albopictus eggs occurred with dW + Th. There was no difference between treatments in A. aegypti (P = 0.4320) and A. albopictus (P = 0.7179). In the field, the highest mean number of eggs for both species were obtained with gI + Ss, and the lowest values were obtained with gI + P (P = 0.0124). The treatments can be applied to both the surveillance and the control, but ovitraps with biological larvicide Bti were more effective and safer considering the number of eggs laid and selectivity of pathogens for mosquitoes.     

Genetic sexing strains for the population suppression of the mosquito vector Aedes aegypti

Aedes aegypti is the primary vector of arthropod-borne viruses including dengue, chikungunya and Zika. Vector population control methods are reviving to impede disease transmission. An efficient sex separation for male-only releases is crucial for area-wide mosquito population suppression strategies. Here, we report on the construction of two genetic sexing strains using red- and white-eye colour mutations as selectable markers. Quality control analysis showed that the Red-eye genetic sexing strains (GSS) is better and more genetically stable than the White-eye GSS. The introduction of an irradiation-induced inversion (Inv35) increases genetic stability and reduces the probability of female contamination of the male release batches. Bi-weekly releases of irradiated males of both the Red-eye GSS and the Red-eye GSS/Inv35 fully suppressed target laboratory cage populations within six and nine weeks, respectively. An image analysis algorithm allowing sex determination based on eye colour identification at the pupal stage was developed. The next step is to automate the Red-eye-based genetic sexing and validate it in pilot trials prior to its integration in large-scale population suppression programmes.This article is part of the theme issue ‘Novel control strategies for mosquito-borne diseases’.     

Zika病毒感染的实验室诊断

Zika病毒是一种新现虫媒黄病毒,近期在美洲暴发流行,并有向全球扩散的趋势,已成为国际关注的突发公共卫生事件。Zika病毒感染的临床诊断主要依据实验室检测结果。本文就Zika病毒的核酸检测、抗原和抗体检测、病毒分离鉴定等方面进行综述。     

寨卡病毒蛋白结构与功能研究进展

2015年以来,南美暴发大规模寨卡疫情,因其与新生儿小头症等严重神经发育疾病密切相关,被世界卫生组织列为国际关注的突发公共卫生事件。与其他虫媒黄病毒类似,寨卡病毒为单股正链RNA病毒,其基因组编码的3种结构蛋白构成病毒颗粒,7种非结构蛋白参与病毒复制生活周期的调控。在全球科学家的共同努力下,寨卡病毒蛋白结构与功能的研究取得了突破性进展,极大地促进研究者对病毒复制与致病机制的认识,也为疫苗和药物研发提供了重要科学依据和潜在靶标。本文将对寨卡病毒蛋白的结构与功能的最新研究进展作一综述,并讨论当前面临的挑战和机遇。     

Recent Advances in Animal Models of Zika Virus Infection

An infection by Zika virus(ZIKV), a mosquito-borne flavivirus, broke out in South American regions in 2015, and recently showed a tendency of spreading to North America and even worldwide. ZIKV was first detected in 1947 and only 14 human infection cases were reported until 2007. This virus was previously observed to cause only mild flu-like symptoms.However, recent ZIKV infections might be responsible for the increasing cases of neurological disorders such as GuillainBarre′ syndrome and congenital defects, including newborn microcephaly. Therefore, researchers have established several animal models to study ZIKV transmission and pathogenesis, and test therapeutic candidates. This review mainly summarizes the reported animal models of ZIKV infection, including mice and non-human primates.