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      Discovering New Medicines Targeting Helicases: Challenges and Recent Progress

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          Abstract

          Helicases are ubiquitous motor proteins that separate and/or rearrange nucleic acid duplexes in reactions fueled by adenosine triphosphate (ATP) hydrolysis. Helicases encoded by bacteria, viruses, and human cells are widely studied targets for new antiviral, antibiotic, and anticancer drugs. This review summarizes the biochemistry of frequently targeted helicases. These proteins include viral enzymes from herpes simplex virus, papillomaviruses, polyomaviruses, coronaviruses, the hepatitis C virus, and various flaviviruses. Bacterial targets examined include DnaB-like and RecBCD-like helicases. The human DEAD-box protein DDX3 is the cellular antiviral target discussed, and cellular anticancer drug targets discussed are the human RecQ-like helicases and eIF4A. We also review assays used for helicase inhibitor discovery and the most promising and common helicase inhibitor chemotypes, such as nucleotide analogues, polyphenyls, metal ion chelators, flavones, polycyclic aromatic polymers, coumarins, and various DNA binding pharmacophores. Also discussed are common complications encountered while searching for potent helicase inhibitors and possible solutions for these problems.

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          Most cited references203

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          Molecular beacons: probes that fluoresce upon hybridization.

          We have developed novel nucleic acid probes that recognize and report the presence of specific nucleic acids in homogeneous solutions. These probes undergo a spontaneous fluorogenic conformational change when they hybridize to their targets. Only perfectly complementary targets elicit this response, as hybridization does not occur when the target contains a mismatched nucleotide or a deletion. The probes are particularly suited for monitoring the synthesis of specific nucleic acids in real time. When used in nucleic acid amplification assays, gene detection is homogeneous and sensitive, and can be carried out in a sealed tube. When introduced into living cells, these probes should enable the origin, movement, and fate of specific mRNAs to be traced.
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            Pathogenic Escherichia coli.

            Few microorganisms are as versatile as Escherichia coli. An important member of the normal intestinal microflora of humans and other mammals, E. coli has also been widely exploited as a cloning host in recombinant DNA technology. But E. coli is more than just a laboratory workhorse or harmless intestinal inhabitant; it can also be a highly versatile, and frequently deadly, pathogen. Several different E. coli strains cause diverse intestinal and extraintestinal diseases by means of virulence factors that affect a wide range of cellular processes.
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              Structure and mechanism of helicases and nucleic acid translocases.

              Helicases and translocases are a ubiquitous, highly diverse group of proteins that perform an extraordinary variety of functions in cells. Consequently, this review sets out to define a nomenclature for these enzymes based on current knowledge of sequence, structure, and mechanism. Using previous definitions of helicase families as a basis, we delineate six superfamilies of enzymes, with examples of crystal structures where available, and discuss these structures in the context of biochemical data to outline our present understanding of helicase and translocase activity. As a result, each superfamily is subdivided, where appropriate, on the basis of mechanistic understanding, which we hope will provide a framework for classification of new superfamily members as they are discovered and characterized.
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                Author and article information

                Journal
                SLAS Discov
                SLAS Discov
                Slas Discovery
                Society for Laboratory Automation and Screening. Published by Elsevier Inc.
                2472-5552
                2472-5560
                25 April 2022
                August 2013
                25 April 2022
                : 18
                : 7
                : 761-781
                Affiliations
                [ 1 ]Department of Chemistry & Biochemistry, University of Wisconsin–Milwaukee, Milwaukee, WI, USA
                Author notes
                [*] [* ]David N. Frick, PhD, Department of Chemistry & Biochemistry, University of Wisconsin–Milwaukee, 3210 N Cramer St, Milwaukee, WI 53211, USA. Email: frickd@uwm.edu
                Article
                S2472-5552(22)07529-3
                10.1177/1087057113482586
                4427233
                23536547
                ebb9134d-ed5b-470b-b5d6-715ad1ee6026
                Copyright © 2013 Society for Laboratory Automation and Screening. Published by Elsevier Inc.

                Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active.

                History
                : 1 December 2012
                : 28 January 2013
                : 22 February 2013
                Categories
                Review Article

                motor protein,atpase,rna binding proteins,molecular probes,antivirals,antibiotic,anticancer

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