Work

Scaffold Morphing Approach To Expand the Toolbox of Broad-Spectrum Antivirals Blocking Dengue/Zika Replication

Year: 2019

Type: article

Abstract: We have recently discovered a family of 2,6-diaminopurine derivatives acting as DENV inhibitors by targeting an allosteric pocket on the thumb of the viral NS5 polymerase. Although the following target-based optimization allowed conversion of the hits into broad-spectrum DENV/ZIKV inhibitors, no improvement of the antiviral potency was reached. Herein, we applied a phenotypic scaffold-morphing approach to explore additional biologically relevant chemical space around the original hits by converting the flat purine derivatives into more complex chemotypes characterized by a higher degree of saturation. A new microwave-assisted one-pot three-step protocol was also developed to quickly generate chemotypes 6 and 7 . Cell-based phenotypic screening allowed identification of promising antiflaviviral agents belonging to different chemotypes. Compound 9d emerged as the most promising broad-spectrum antiviral, being 6 times more potent than ribavirin (RBV) against DENV and 3 times more potent than 7-deaza-2′-C-methyladenosine (7DMA) against ZIKV with good selectivity indexes (>46 and >41, respectively).

Source: ACS Medicinal Chemistry Letters

DOI: 10.1021/acsmedchemlett.8b00583

Authors: Paolo Vincetti, Suzanne J. F. Kaptein, Gabriele Costantino, Johan Neyts, Marco Radi

Institutions: University of Parma, Rega Institute for Medical Research, KU Leuven

Language: English

Topic: Mosquito-borne diseases and control

Subfield: Public Health, Environmental and Occupational Health

Field: Medicine

Domain: Health Sciences

SDG: Good health and well-being

Open Access status: green

Funder: Università degli Studi di Parma