Adenosine Analog NITD008 Is a Potent Inhibitor of Zika Virus

Deng, Yong Qiang; Zhang, Na Na; Li, Chun Feng; Tian, Min; Hao, Jia; Xie, Xu Ping; Shi, Pei Yong; Qin, Cheng‐Feng

doi:10.1093/ofid/ofw175

Cited by 133 publications

(110 citation statements)

References 16 publications

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“…Current small-molecule drugs against flaviviruses include NITD008, a nucleoside analog targeting viral polymerases that has been shown to exhibit potent antiviral activity against DENV, WNV, hepatitis C virus, and, more recently, ZIKV in Vero cells (22,23). Therefore, we next evaluated if this drug can block ZIKV replication in HSeCs.…”

Section: Resultsmentioning

confidence: 99%

“…Furthermore, our data demonstrating the dose-dependent effect of a well-tested antiflavivirus compound, NITD008, on blocking ZIKV replication in SCs are encouraging and warrant future in vivo studies to test whether this drug can cross the SCB and clear testicular ZIKV infection. A recent study reported the inhibition of ZIKV by NITD008 in Vero cells and in a mouse model; however, that study did not examine the ability of this drug to clear testicular infections (22). Our in vitro model of the SCB not only can be used as a tool to characterize testicular infections by other viruses, including Ebola virus, but also will allow the rapid testing of new antiviral drugs to cross the SCB and mitigate infection in the seminiferous tubules.…”

Section: Discussionmentioning

confidence: 99%

“…UV-ZIKV was generated by exposing the virus stock to UV radiation for 10 min (Stratalinker 2400; Stratagene) as described previously for WNV and confirmed by a plaque assay (37). In some experiments, HSeCs were infected with DENV2 (New Guinea C strain) or ZIKV in the presence of NITD008, an antiflavivirus compound, at different concentrations, prepared as described previously (22).…”

Section: Discussionmentioning

confidence: 99%

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Zika Virus Infects Human Sertoli Cells and Modulates the Integrity of the In Vitro Blood-Testis Barrier Model

Siemann

Strange

Maharaj

et al. 2017

J Virol

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117

101

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Confirmed reports of Zika virus (ZIKV) in human seminal fluid for months after the clearance of viremia suggest the ability of ZIKV to establish persistent infection in the seminiferous tubules, an immune-privileged site in the testis protected by the blood-testis barrier, also called the Sertoli cell (SC) barrier (SCB). However, cellular targets of ZIKV in human testis and mechanisms by which the virus enters seminiferous tubules remain unclear. We demonstrate that primary human SCs were highly susceptible to ZIKV compared to the closely related dengue virus and induced the expression of alpha interferon (IFN-␣), key cytokines, and cell adhesion molecules (vascular cell adhesion molecule 1 [VCAM-1] and intracellular adhesion molecule 1 [ICAM-1]). Furthermore, using an in vitro SCB model, we show that ZIKV was released on the adluminal side of the SCB model with a higher efficiency than in the blood-brain barrier model. ZIKV-infected SCs exhibited enhanced adhesion of leukocytes that correlated with decreases in SCB integrity. ZIKV infection did not affect the expression of tight and adherens junction proteins such as ZO-1, claudin, and JAM-A; however, exposure of SCs to inflammatory mediators derived from ZIKV-infected macrophages led to the degradation of the ZO-1 protein, which correlated with increased SCB permeability. Taken together, our data suggest that infection of SCs may be one of the crucial steps by which ZIKV gains access to the site of spermatozoon development and identify SCs as a therapeutic target to clear testicular infections. The SCB model opens up opportunities to assess interactions of SCs with other testicular cells and to test the ability of anti-ZIKV drugs to cross the barrier.IMPORTANCE Recent outbreaks of ZIKV, a neglected mosquito-borne flavivirus, have identified sexual transmission as a new route of disease spread, which has not been reported for other flaviviruses. To be able to sexually transmit for months after the clearance of viremia, ZIKV must establish infection in the seminiferous tubules, the site of spermatozoon development. However, little is known about the cell types that support ZIKV infection in the human testis. Currently, there are no models to study mechanisms of virus persistence in the seminiferous tubules. We provide evidence that ZIKV infection of human Sertoli cells, which are an important component of the seminiferous tubules, is robust and induces a strong antiviral response. The use of an in vitro Sertoli cell barrier to describe how ZIKV or inflammatory mediators derived from ZIKV-infected macrophages compromise barrier integrity will enable studies to explore the interactions of other testicular cells with Sertoli cells and to test novel antivirals for clearing testicular ZIKV infection.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Zika Virus Infects Human Sertoli Cells and Modulates the Integrity of the In Vitro Blood-Testis Barrier Model

Siemann

Strange

Maharaj

et al. 2017

J Virol

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117

101

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“…The in vitro antiviral activity of temoporfin to a contemporary ZIKV strain GZ01 [72] (isolated from patient returned from Venezuela in 2016) was carried out as previously described [73]. Briefly, Vero cells were infected with Zika virus GZ01/2016 strain at a MOI of 0.1 and treated with 10-fold serial dilutions of temoporfin.…”

Section: Viral Titer Reduction Assaysmentioning

confidence: 99%

Existing drugs as broad-spectrum and potent inhibitors for Zika virus by targeting NS2B-NS3 interaction

et al. 2017

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Recent outbreaks of Zika virus (ZIKV) highlight an urgent need for therapeutics.The protease complex NS2B-NS3 plays essential roles during flaviviral polyprotein processing, and thus represents an attractive drug target. Here, we developed a split luciferase complementation-based high-throughput screening assay to identify orthosteric inhibitors that directly target flavivirus NS2B-NS3 interactions. By screening a total of 2 816 approved and investigational drugs, we identified three potent candidates, temoporfin, niclosamide, and nitazoxanide, as flavivirus NS2B-NS3 interaction inhibitors with nanomolar potencies. Significantly, the most potent compound, temoporfin, not only inhibited ZIKV replication in human placental and neural progenitor cells, but also prevented ZIKV-induced viremia and mortality in mouse models. Structural docking suggests that temoporfin potentially binds NS3 pockets that hold critical NS2B residues, thus inhibiting flaviviral polyprotein processing in a non-competitive manner. As these drugs have already been approved for clinical use in other indications either in the USA or other countries, they represent promising and easily developed therapies for the management of infections by ZIKV and other flaviviruses.

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“…Three studies have used susceptible AG129 or A129 mice to demonstrate that compounds targeting the viral RNA-dependent RNA polymerase (RdRp) can reduce the viral burden in tissues and reduce or delay virus-induced morbidity and mortality following inoculation of ZIKV (29,30,83). In addition, treatment for 1 week with sofosbuvir, an RdRp inhibitor approved by the Food and Drug Administration for the treatment of hepatitis C virus infection (84), beginning 1 day after infection with a mouse-adapted strain of ZIKVDakar 41519 improved the survival rate of C57BL/6 mice treated with an anti-IFNAR1 MAb (85).…”

mentioning

confidence: 99%

Animal Models of Zika Virus Infection, Pathogenesis, and Immunity

Morrison

Diamond

2017

J Virol

236

239

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Zika virus (ZIKV) is an emerging mosquito-transmitted flavivirus that now causes epidemics affecting millions of people on multiple continents. The virus has received global attention because of some of its unusual epidemiological and clinical features, including persistent infection in the male reproductive tract and sexual transmission, an ability to cross the placenta during pregnancy and infect the developing fetus to cause congenital malformations, and its association with Guillain-Barré syndrome in adults. This past year has witnessed an intensive effort by the global scientific community to understand the biology of ZIKV and to develop pathogenesis models for the rapid testing of possible countermeasures. Here, we review the recent advances in and utility and limitations of newly developed mouse and nonhuman primate models of ZIKV infection and pathogenesis.

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Adenosine Analog NITD008 Is a Potent Inhibitor of Zika Virus

Cited by 133 publications

References 16 publications

Zika Virus Infects Human Sertoli Cells and Modulates the Integrity of the In Vitro Blood-Testis Barrier Model

Zika Virus Infects Human Sertoli Cells and Modulates the Integrity of the In Vitro Blood-Testis Barrier Model

Existing drugs as broad-spectrum and potent inhibitors for Zika virus by targeting NS2B-NS3 interaction

Animal Models of Zika Virus Infection, Pathogenesis, and Immunity

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