8E4S

The crystal structure of I38T mutant PA endonuclease (2009/H1N1/CALIFORNIA) in complex with compound SJ001023034

Summary for 8E4S

• Entry DOI: 10.2210/pdb8e4s/pdb
• Descriptor: Polymerase acidic protein, MANGANESE (II) ION, 5-hydroxy-6-oxo-N-[2-(pyridin-4-yl)ethyl]-2-{[2-(trifluoromethyl)phenyl]methyl}-3,6-dihydropyrimidine-4-carboxamide, ... (6 entities in total)
• Functional Keywords: nuclease, influenza, inhibitor resistance, viral protein
• Biological source: Influenza A virus (A/Luxembourg/43/2009(H1N1)); More
• Total number of polymer chains: 1
• Total formula weight: 24525.53

Authors

Cuypers, M.G.,Slavish, J.P.,Rankovic, Z.,White, S.W. (deposition date: 2022-08-18, release date: 2022-09-21, Last modification date: 2024-04-03)

Primary citation

Slavish, P.J.,Cuypers, M.G.,Rimmer, M.A.,Abdolvahabi, A.,Jeevan, T.,Kumar, G.,Jarusiewicz, J.A.,Vaithiyalingam, S.,Jones, J.C.,Bowling, J.J.,Price, J.E.,DuBois, R.M.,Min, J.,Webby, R.J.,Rankovic, Z.,White, S.W.
Chemical scaffold recycling: Structure-guided conversion of an HIV integrase inhibitor into a potent influenza virus RNA-dependent RNA polymerase inhibitor designed to minimize resistance potential.
Eur.J.Med.Chem., 247:115035-115035, 2023

PubMed Abstract: Influenza is one of the leading causes of disease-related mortalities worldwide. Several strategies have been implemented during the past decades to hinder the replication cycle of influenza viruses, all of which have resulted in the emergence of resistant virus strains. The most recent example is baloxavir marboxil, where a single mutation in the active site of the target endonuclease domain of the RNA-dependent-RNA polymerase renders the recent FDA approved compound ∼1000-fold less effective. Raltegravir is a first-in-class HIV inhibitor that shows modest activity to the endonuclease. Here, we have used structure-guided approaches to create rationally designed derivative molecules that efficiently engage the endonuclease active site. The design strategy was driven by our previously published structures of endonuclease-substrate complexes, which allowed us to target functionally conserved residues and reduce the likelihood of resistance mutations. We succeeded in developing low nanomolar equipotent inhibitors of both wild-type and baloxavir-resistant endonuclease. We also developed macrocyclic versions of these inhibitors that engage the active site in the same manner as their 'open' counterparts but with reduced affinity. Structural analyses provide clear avenues for how to increase the affinity of these cyclic compounds.

PubMed: 36603507
DOI: 10.1016/j.ejmech.2022.115035

Experimental method

X-RAY DIFFRACTION (2.4 Å)