Development of Small Molecules as Broad-spectrum Filoviral Entry Inhibitors

Ebola (EBOV) and Marburg (MARV) filoviruses are priority infectious agents due to their high pathogenicity and lethality in infected patients. The current lack of pan-filoviral therapeutics exemplifies the need for effective treatments against diverse filoviruses. The filoviral glycoprotein (GP) has proven to be a drug-targetable site as it is conserved amongst all filoviruses and is used to mediate several steps in filoviral entry. In the effort to develop broad-spectrum antifilovirals, a series of N-substituted pyrrole-based heterocycles and elacestrant derivatives were developed to target GP and effectively inhibit diverse filoviral entry in a pseudovirus assay. Selectivity, potency, and metabolic stability of these viral entry inhibitors were improved by introducing structural modifications. In addition, antiviral activity was validated using replication-competent EBOV and MARV, mutational analysis was used to identify the suggested EBOV GP binding region, and antiviral counter-screens demonstrated reduced off-target activity for these filoviral entry inhibitors. Excellent activity coupled with favorable drug-like properties support these entry inhibitors as promising broad-spectrum antifilovirals.

Author dc:creator

• Destiny Durante (19339059)

• Chemistry
• Pharmaceutical

Statement dc:rights

• In Copyright
• Open Access after 2027-09-01

DOI dc:identifier

https://doi.org/10.25417/uic.30426376.v1

OAI identifier oai:identifier

oai:figshare.com:article/30426376