New Molecular Tweezers Against Neurological Disorders And Viral Infections

Summary

UCLA researchers in the Department of Neurology with an international team of scientists have developed several new molecular tweezer derivatives with novel synthesis methods that significantly improved the therapeutic efficacy and pharmacokinetic characteristics of the drug candidates.

Background

Protein aggregation is critical in the pathologic mechanism of various neurodegenerative diseases, such as Alzheimer’s and Parkinson’s, as well as rare orphan diseases, such as multiple system atrophy, amyotrophic lateral sclerosis, and familial amyloidotic polyneuropathy.  These diseases bring high financial burdens globally and effective therapeutics are gravely needed.

Molecular tweezers are a type of small molecule drug candidates that efficiently inhibit abnormal protein aggregation, toxicity, and cell-to-cell spreading.  The earlier lead compound, CLR01, covered by UCLA case 2008-489, has shown great therapeutic effects in various animal models, preventing the formation of protein aggregates while enhancing the clearance of already formed aggregations.  Continuous efforts have been made since then to further improve CLR01 for FDA testing and clinical trials.

Innovation

UCLA researchers in the Department of Neurology with an international team of scientists have developed several new molecular-tweezer derivatives using novel synthetic methods.  The versatility of the molecular tweezers is significantly increased with the new synthesis methods.  Several of the new molecular tweezer derivatives have shown improved pharmacokinetic characteristics, including improved oral bioavailability and blood-brain barrier penetration.

Applications

• Therapeutics in Alzheimer’s disease
• Therapeutics in Parkinson’s disease
• Therapeutics in other neurodegenerative diseases
• Therapeutics in rare orphan diseases
• Anti-Viral therapeutics against enveloped viruses

Advantages

• Improved lysine and arginine affinities
• Improved blood-brain barrier (BBB) penetration
• Improved oral bioavailability

Patent Status

Related Materials

• Fokkens, M.; Schrader, T.; Klärner, F. G., A molecular tweezer for lysine and arginine. J. Am. Chem. Soc. 2005, 127 (41), 14415-14421.
• Sinha, S.; Lopes, D. H.; Du, Z.; Pang, E. S.; Shanmugam, A.; Lomakin, A.; Talbiersky, P.; Tennstaedt, A.; McDaniel, K.; Bakshi, R.; Kuo, P. Y.; Ehrmann, M.; Benedek, G. B.; Loo, J. A.; Klärner, F. G.; Schrader, T.; Wang, C.; Bitan, G., Lysine-specific molecular tweezers are broad-spectrum inhibitors of assembly and toxicity of amyloid proteins. J. Am. Chem. Soc. 2011, 133 (42), 16958-69.
• Schrader, T.; Bitan, G.; Klärner, F. G., Molecular tweezers for lysine and arginine - powerful inhibitors of pathologic protein aggregation. Chem Commun (Camb) 2016, 52 (76), 11318-34.
• Röcker, A. E.; Müller, J. A.; Dietzel, E.; Harms, M.; Kruger, F.; Heid, C.; Sowislok, A.; Riber, C. F.; Kupke, A.; Lippold, S.; von Einem, J.; Beer, J.; Knoll, B.; Becker, S.; Schmidt-Chanasit, J.; Otto, M.; Vapalahti, O.; Zelikin, A. N.; Bitan, G.; Schrader, T.; Munch, J., The molecular tweezer CLR01 inhibits Ebola and Zika virus infection. Antiviral Res 2018, 152, 26-35.