Development of Potent Antiviral Drugs Inspired by Viral Hexameric DNA-Packaging Motors with Revolving Mechanism

Abstract

The intracellular parasitic nature of viruses and the emergence of antiviral drug resistance necessitate the development of new potent antiviral drugs. Recently, a method for developing potent inhibitory drugs by targeting biological machines with high stoichiometry and a sequential-action mechanism was described. Inspired by this finding, we reviewed the development of antiviral drugs targeting viral DNA-packaging motors. Inhibiting multisubunit targets with sequential actions resembles breaking one bulb in a series of Christmas lights, which turns off the entire string. Indeed, studies on viral DNA packaging might lead to the development of new antiviral drugs. Recent elucidation of the mechanism of the viral double-stranded DNA (dsDNA)-packaging motor with sequential one-way revolving motion will promote the development of potent antiviral drugs with high specificity and efficiency. Traditionally, biomotors have been classified into two categories: linear and rotation motors. Recently discovered was a third type of biomotor, including the viral DNA-packaging motor, beside the bacterial DNA translocases, that uses a revolving mechanism without rotation. By analogy, rotation resembles the Earth's rotation on its own axis, while revolving resembles the Earth's revolving around the Sun (see animations at http://rnanano.osu.edu/movie.html). Herein, we review the structures of viral dsDNA-packaging motors, the stoichiometries of motor components, and the motion mechanisms of the motors. All viral dsDNA-packaging motors, including those of dsDNA/dsRNA bacteriophages, adenoviruses, poxviruses, herpesviruses, mimiviruses, megaviruses, pandoraviruses, and pithoviruses, contain a high-stoichiometry machine composed of multiple components that work cooperatively and sequentially. Thus, it is an ideal target for potent drug development based on the power function of the stoichiometries of target complexes that work sequentially. Viruses reproduce themselves in host cells. Their intracellular parasitic nature poses a great challenge to antiviral drug development. Nevertheless, significant progress in antiviral drug discovery, such as new treatments for HIV (1), hepatitis B virus (2), herpesvirus (3), and influenza virus (4), has been made. Even though different approaches to new drug development, such as improving drug target binding affinity (5) and finding new targets with novel pharmacological mechanisms (6), have been explored, new infectious pandemic viruses that greatly threaten human health still emerge sporadically. In addition, the emergence of drug resistance necessitates new drug development. Highly potent drugs with elevated specificity are needed for overcoming viral diseases.In viral reproduction, the key step of genome packaging is usually accomplished by a biomotor using ATP. Linear doublestranded DNA (dsDNA) or dsRNA viruses package their genomes into preformed procapsids. This group includes dsDNA/dsRNA bacteriophages (7), adenoviruses (8), poxviruses (9, 120), herpesviruses (10, 11), mimiviruses, megavir...

An Arginine Finger Regulates the Sequential Action of Asymmetrical Hexameric ATPase in the Double-Stranded DNA Translocation Motor

“…Furthermore, the conclusion that coordination is provided by an asymmetrical hexamer was supported by structural computation, X-ray diffraction, and cryo-electron microscopy (cryo-EM) imaging of other hexameric ATPase systems ( Fig. 7 ) ( 71 , 75 – 80 ). These results could provide some clues as to why the asymmetrical hexameric ATPase of gp16 of ϕ29 and gp17 of T4 was previously interpreted as a pentameric configuration by cryo-EM.…”

“…The ATPase hexameric ring exerts a force, pushing the dsDNA in a sequential manner to advance through the dodecamer channel, which acts as a one-way valve as reported for the phi29 motor ( 5 , 19 , 62 , 70 , 71 ). The interest in the sequential revolving mechanism lies in the fact that it elegantly integrates all the known functional and structural information about the packaging core (the ATPase, pRNA, and connector).…”

High resolution structure of hexameric herpesvirus DNA-packaging motor elucidates revolving mechanism and ends 20-year fervent debate

“…The mechanism of dsDNA processing can be extended to ATPase motors in protein processing, peptide transportation, and trafficking of other macromolecules. The elucidation of structure and mechanism of the asymmetrical hexameric dsDNA transportation motor with a revolving mechanism will provide a prototype for the construction of a revolving motor or nanomotor with high efficiency in energy conversion and provide an excellent substrate for the design of potent inhibitory drugs to treat cancer and other diseases (Goldner et al, 2011;Shu et al, 2015;Pi et al, 2016a;Pi et al, 2016b;Acosta et al, 2020). The revolving mechanism for the motion of objects along a helical chain provides a hint at the design of new moving machines along a track, such as that used by roller coasters, trolley cars or rocket launchers to depart from a helical track without the need for the object to rotate.…”

Design and synthesis of thiadiazolo-carboxamide bridged β-carboline-indole hybrids: DNA intercalative topo-IIα inhibition with promising antiproliferative activity

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