Discovery of Multitarget Antivirals Acting on Both the Dengue Virus NS5-NS3 Interaction and the Host Src/Fyn Kinases

Abstract

This study describes the discovery of novel dengue virus inhibitors targeting both a crucial viral protein-protein interaction and an essential host cell factor as a strategy to reduce the emergence of drug resistance. Starting from known c-Src inhibitors, a virtual screening was performed to identify molecules able to interact with a recently discovered allosteric pocket on the dengue virus NS5 polymerase. The selection of cheap-to-produce scaffolds and the exploration of the biologically relevant chemical space around them suggested promising candidates for chemical synthesis. A series of purines emerged as the most interesting candidates able to inhibit virus replication at low micromolar concentrations with no significant toxicity to the host cell. Among the identified antivirals, compound 16i proved to be 10 times more potent than ribavirin, showed a better selectivity index and represents the first-in-class DENV-NS5 allosteric inhibitor able to target both the virus NS5-NS3 interaction and the host kinases c-Src/Fyn.

Insights into intercontinental spread of Zika virus

“…Both cryo-electron microscopy and crystallization analyses supported the role of an asparagine residue as a glycosylation site for host cell attachment [14,15]. Envelope glycoproteins, capsid protein NS3 helicase and NS5 polymerase are the major targets of flaviviruses for antiviral agent development [16–18]. Using NS5 nucleotide sequences, ZIKV could divided into three major lineages: East Africa, West Africa and Asian[19].…”

Discovery of New Potential Anti‐Infective Compounds Based on Carbonic Anhydrase Inhibitors by Rational Target‐Focused Repurposing Approaches

“…The analysis revealed that, among others, the most abundant fragments are 2‐aminothiazole ( 1 ), 2‐phenylcyclopropane‐1‐amino ( 2 ), 2‐hydroxypyridinium ( 3 ), pyridine‐ N ‐oxide ( 4 ), cyclopropanecarboxylic acid( 5 ), and benzoic acid ( 6 ; Figure ). Taking into account that most of the compounds available in our lab were designed as antimicrobial agents or inhibitors of metalloenzymes, we decided to focus our attention on all of those targets that satisfied the following criteria: 1) they are metalloenzymes ubiquitously expressed in most living organisms, and 2) there are reported inhibitors that are characterized by fragments similar to those present in our library. An extensive knowledge‐based literature search allowed us to identify the carbonic anhydrase superfamily as an eligible protein class .…”

“…The affinity of our compounds, either pyridine‐ N ‐oxides or phenylcyclopropane carboxylates, is much lower than that of reference compounds such as AAZ. Nevertheless, it must be stressed that our compounds come from a recycling approach and that they were optimized against very different targets . We are confident that some of them can still be highly optimized against microbial CAs.…”

Identification of Broad‐Spectrum Dengue/Zika Virus Replication Inhibitors by Functionalization of Quinoline and 2,6‐Diaminopurine Scaffolds

“…Previously, we reported the discovery of the first multitarget inhibitors (i.e., 1 and 2 ) that inhibited DENV replication at low‐micromolar concentrations (Figure ) by interfering with the NS3–NS5 interaction . These inhibitors were rationally designed by repurposing Src kinase scaffolds to bind NS5 cavity B, thus aiming for the contemporary inhibition of Src/Fyn kinases and NS3–NS5 interaction, which are both involved in DENV replication .…”