The Rational Design of Antiviral Agents

Grollman, Arthur P.; Horwitz, Susan Band

doi:10.1016/b978-0-12-060302-2.50014-2

Cited by 1 publication

(2 citation statements)

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“…Seminal studies on the remarkable antiviral properties of triphenylmethane dyes discovered over four decades ago [21][22][23]25,26] have prompted investigations of their potential use as lead compounds in targeting SARS-CoV-2. In the search for novel activities via HTS assays utilizing the LOPAC arsenal of compounds, ATA is often identified among positive hits in drug discovery campaigns, including those in the quest for SARS-CoV-2 therapies [34].…”

Section: Discussionmentioning

confidence: 99%

“…The synthesis of ATA traces its origin to 1892 as the primary product of a condensation reaction between salicylic acid and formaldehyde in the presence of sulfuric acid and nitrite ion [16]. Multiple applications have been reported since its discovery, including seminal studies conducted during the 1960s and 1970s [17] that explored ATA as an inhibitor of protein synthesis in eukaryotes while elucidating specific mechanisms of several antiviral and antibiotic compounds at the ribosomal level [18][19][20][21][22][23][24][25][26]. Harnessing insights gained from parallel investigations on emetine [17][18][19]24,27], Grollman and colleagues focused particular attention on the initiation of viral protein synthesis as a target for anti-viral drug design.…”

Section: Introductionmentioning

confidence: 99%

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Characterization of Aurintricarboxylic Acid (ATA) Interactions with Plasma Transporter Protein and SARS-CoV-2 Viral Targets: Correlation of Functional Activity and Binding Energetics

Minetti

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Hashimoto

et al. 2022

Life

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In an effort to identify functional-energetic correlations leading to the development of efficient anti-SARS-CoV-2 therapeutic agents, we have designed synthetic analogs of aurintricarboxylic acid (ATA), a heterogeneous polymeric mixture of structurally related linear homologs known to exhibit a host of biological properties, including antiviral activity. These derivatives are evaluated for their ability to interact with a plasma transporter protein (human serum albumin), eukaryotic (yeast) ribosomes, and a SARS-CoV-2 target, the RNA-dependent RNA polymerase (RdRp). The resultant data are critical for characterizing drug distribution, bioavailability, and effective inhibition of host and viral targets. Promising lead compounds are selected on the basis of their binding energetics which have been characterized and correlated with functional activities as assessed by inhibition of RNA replication and protein synthesis. Our results reveal that the activity of heterogeneous ATA is mimicked by linear compounds of defined molecular weight, with a dichlorohexamer salicylic-acid derivative exhibiting the highest potency. These findings are instrumental for optimizing the design of structurally defined ATA analogs that fulfill the requirements of an antiviral drug with respect to bioavailability, homogeneity, and potency, thereby expanding the arsenal of therapeutic regimens that are currently available to address the urgent need for effective SARS-CoV-2 treatment strategies.

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