Discovering New Medicines Targeting Helicases: Challenges and Recent Progress

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.

Lentiviral DDX46 knockdown inhibits growth and induces apoptosis in human colorectal cancer cells

“…Cancer initiation is a long-term process requiring accumulation of incorrect RNAs and proteins. Dysregulation of protein synthesis could be caused by abnormal activity of the RNA helicases needed for translation (Jin et al, 2013;Shadrick et al, 2013). The expression of DDX46 is normally under tight control.…”

Biochemical and cell biological assays to identify and characterize DNA helicase inhibitors

“…Screening and characterization of biologically active small molecules that modulate the DNA unwinding function of a target helicase represents a unique approach to studying helicase function in human cells [4,5,8]. We have used this approach to investigate the molecular and cellular functions of the WRN helicase-nuclease defective in the premature aging disorder Werner syndrome.…”

“…Because DNA helicases play a unique and early role in a number of DNA damage response and DNA repair pathways especially in dividing cells, we hypothesize that they represent a useful target to exploit synthetic lethal relationships with other DNA damaging agents and/or in specific mutant backgrounds. In a 2013 review, the Frick laboratory provided an overview of the helicase inhibitors described to date with an emphasis on published work that used screens to identify compounds that modulate the human RecQ helicases or the RNA helicase elongation initiation factor 4A [8]. In the current review for this special Methods collection on DNA helicases, we have focused on the actual experimental approaches and assays we employed to perform a small molecule screen for inhibitors of the Werner syndrome helicase implicated in the premature aging disorder Werner syndrome [9-11].…”

Versatility of 7-Substituted Coumarin Molecules as Antimycobacterial Agents, Neuronal Enzyme Inhibitors and Neuroprotective Agents

“…Apart from an interaction with gyrase, bacterial DNA helicase is another suggested target of selected coumarin derivatives [13][14][15]. Similar to other non-classical coumarin antibiotics, the 7-position on these coumarin derivatives does not contain an amino sugar, but rather a moiety able to undergo hydrophobic interactions with the target site [13][14][15].…”

“…Similar to other non-classical coumarin antibiotics, the 7-position on these coumarin derivatives does not contain an amino sugar, but rather a moiety able to undergo hydrophobic interactions with the target site [13][14][15]. Compound 22 (Figure 1), a 4,8-dimethyl-3-propionic acid coumarin derivative with a 2-(4-chloro[1,1-biphenyl]4-yl)ethyl substitution on the 7-position was the most active helicase inhibitor in this series of 7-substituted biphenyl coumarin derivatives [14].…”