DEAD-box RNA Helicase DDX3: Functional Properties and Development of DDX3 Inhibitors as Antiviral and Anticancer Drugs.

Inna L Karpenko,Marina K Kukhanova,Alexander V Ivanov

doi:10.3390/molecules25041015

Inna L Karpenko, Marina K Kukhanova + Show 1 more

Open Access

https://doi.org/10.3390/molecules25041015

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Abstract

This short review is focused on enzymatic properties of human ATP-dependent RNA helicase DDX3 and the development of antiviral and anticancer drugs targeting cellular helicases. DDX3 belongs to the DEAD-box proteins, a large family of RNA helicases that participate in all aspects of cellular processes, such as cell cycle progression, apoptosis, innate immune response, viral replication, and tumorigenesis. DDX3 has a variety of functions in the life cycle of different viruses. DDX3 helicase is required to facilitate both the Rev-mediated export of unspliced/partially spliced human immunodeficiency virus (HIV) RNA from nucleus and Tat-dependent translation of viral genes. DDX3 silencing blocks the replication of HIV, HCV, and some other viruses. On the other hand, DDX displays antiviral effect against Dengue virus and hepatitis B virus through the stimulation of interferon beta production. The role of DDX3 in different types of cancer is rather controversial. DDX3 acts as an oncogene in one type of cancer, but demonstrates tumor suppressor properties in other types. The human DDX3 helicase is now considered as a new attractive target for the development of novel pharmaceutical drugs. The most interesting inhibitors of DDX3 helicase and the mechanisms of their actions as antiviral or anticancer drugs are discussed in this short review.

Highlights

Cellular proteins and cofactors have attracted much attention as new targets for the development of antiviral/anticancer drugs
More than 300 cellular proteins and co-factors participate in virus replication [2,3], but the most drugs approved by the Food and Drug Administration for the treatment of viral infections include drugs targeting viral enzymes
In spite of the fact that interfering in cellular integrity poses a risk of toxic effects, some effective chemical inhibitors of DDX3 enzymatic activity have been developed, which suppress viral replication in cell cultures and display anticancer activity against a number of cancer types without significant toxicity

Summary

Introduction

Cellular proteins and cofactors have attracted much attention as new targets for the development of antiviral/anticancer drugs. More than 300 cellular proteins and co-factors participate in virus replication [2,3], but the most drugs approved by the Food and Drug Administration for the treatment of viral infections include drugs targeting viral enzymes. DEAD-box helicases attract a lot of attention as a target for the development of anticancer drugs, due to their role as oncogene in different types of tumors [25,26,27]. These data stimulated the synthesis of DDX3 inhibitors as antiviral/anticancer drugs. In order to design DDX3 selective inhibitors, a detailed knowledge of the substrate specificity of the enzyme, crystal structure, biochemical, and enzymatic properties of DDX3 is very essential

Structure of the DDX3 Helicase and Its Enzymatic Properties

Hypothetical Mechanisms of the DDX3 Helicase Role in Viral Replication

Inhibitors of the DDX3 Helicase

Conclusions