Structures of previous measles virus entry inhibitors (30, 31) and hit compound 1.

March 04, 2024

• Title:       

  Structures of previous measles virus entry inhibitors (30, 31) and hit compound 1.

• Image Source:

  Potent non-nucleoside inhibitors of the measles virus RNA-dependent RNA polymerase complex

• Mark:

  Figure 1

• Associated context:

  In previous work, we reported the structure-based development of a MV entry inhibitor, compound 30 (AS-4,^11,12 Figure 1), with an EC₅₀ of 260 nM against the MV-Edmonston (MV- Edm) strain. Because this compound proved to be unstable, we developed nitro analogue 31 (AS-48) with an EC₅₀ of 0.6-3.0 µM (Figure 1) as a shelf-stable alternative. As a consequence, we broadened our search by turning to cell-based high-throughput screening (HTS) to capture small molecules capable of netting both entry inhibitors as well as compounds operating against other proteins critical for viral infection and reproduction. The exercise identified 1-methyl-3-(trifluoromethyl)-N-[4 (pyrrolidinylsulfonyl)phenyl]- 1H-pyrazole-5-carboxamide 1 (16677) (Figure 1) (EC₅₀ ) 250 nM,) as a well-behaved, target-specific inhibitor of MV replication.