Novel redox switch in proteins as therapeutic target

Targeting essential proteins in pathogens is an appealing way to combat infectious diseases. Scientists at the University of Göttingen discovered a novel and until now overlooked on/off switch that seems to be a ubiquitous regulatory element in proteins in all domains of life. They discovered a new class of Lysine–Cysteine redox switch with an NOS bridge, which regulates enzyme function. Ongoing work will focus on small molecules to selectively target and manipulate this novel switch as potential therapeutics.

Challenge

To combat infectious diseases from pathogens like bacteria antibiotics are typically used, but this approach is threatened by evolution of antibiotic resistant pathogens. To identify new treatment options, scientists need to study the structure and mechanism of proteins that are key players in metabolism of the targeted pathogens.

Our Solution

Scientists at the University of Göttingen, Germany investigated a protein from the human pathogen Neisseria gonorrhoeae (Ng) that causes gonorrhea, a bacterial infection with over 100 million cases worldwide. The scientists studied the structure and mechanism of a key protein in the carbon metabolism (transaldolase). By doing so they identified a novel and unique N–O–S bridge. Like the S–S bridge, the N–O–S bridge can stabilize higher-order protein structures, and the formation of the N–O–S bridge is also chemically reversible (by oxidation and reduction = “redox switch”). Accordingly, the N–O–S bridge suggests new regulatory possibilities for proteins. An analysis of the protein structure database further disclosed many other proteins that very likely possess this switch. The new discovery of an adjustable redox switch might lead to the development of small molecules as potential drug candidates.

Structure of the allosteric redox switch in Ng transaldolase (NgTAL) in the oxidized (a) and reduced (b) state. (a) Structure of the Lys8-Cys38 crosslink in the oxidized state containing a covalent NOS bridge. (b) In the reduced state, the covalent NOS bridge is absent. Both Lys8 and Cys38 are chemically unmodified and show several alternative conformations. The electron density observed in close proximity to the sulfur atom of Cys38 is compatible with a physically dissolved dioxygen molecule suggesting that oxidation of this cysteine precedes formation of the covalent crosslink. (c) The NOS bridge is located at the protein surface and is solvent accessible. It is engaged in H-bond interactions with several water (W) molecules as part of an extended hydrogen bonding network further including residues Glu93, Thr97 and Thr101 suggesting a role of these for formation of the NOS linkage. (d) The presumed dioxygen is bound in a small hydrophobic patch close to Ile14 in H-bonding distance to Cys38, suggesting that formation of the Lys8-Cys38 bridge results from initial cysteine oxidation. Source: EP21164101.4.

Advantages

• new regulable target for pathogen treatment (new drug design)
• in silico drug design to enable specificity and sensitivity of new drugs
• development of new drugs to combat antibiotic resistance

Applications

New treatment option for viral or bacterial infectious diseases (e. g. COVID-19 or Gonorrhea).

Development Status

In vitro feasibility studies of the first test substances were successfully completed.

Patent Status

An international patent application has been filed (WO2022200276A1, applicant: Georg August University of Göttingen public law foundation).

References

• WO2022200276A1: Inhibiting protein activity by mimicking a regulatory redox switch.
• Marie Wensien et al.: A lysine–cysteine redox switch with an NOS bridge regulates enzyme function. Nature 2021. DoI: 10.1038/s41586-021-03513-3
• Fabian Rabe von Pappenheim et al.: NOS and SONOS redox switches in proteins. Nature Chemical Biology 2021 (preprint). DoI:10.21203/rs.3.rs-635771/v1)

Contact

Dr. Stefan Uhle
Patent Manager Life Sciences
E-Mail: This email address is being protected from spambots. You need JavaScript enabled to view it.
Tel.: +49 551 30724 154
Reference: BioC-2288-SUG

Tags: Therapy, Life science