Abstract
Lysine-selective molecular tweezers (MTs) are supramolecular host molecules displaying a remarkably broad spectrum of biologic activities. MTs act as inhibitors of the self-assembly and toxicity of amyloidogenic proteins using a unique mechanism. They destroy viral membranes and inhibit infection by enveloped viruses, such as HIV-1 and SARS-CoV-2, by mechanisms unrelated to their action on protein self-assembly. They also disrupt biofilm of Gram-positive bacteria. The efficacy and safety of MTs have been demonstrated in vitro, in cell culture, and in vivo, suggesting that these versatile compounds are attractive therapeutic candidates for various diseases, infections, and injuries. A lead compound called CLR01 has been shown to inhibit the aggregation of various amyloidogenic proteins, facilitate their clearance in vivo, prevent infection by multiple viruses, display potent anti-biofilm activity, and have a high safety margin in animal models. The inhibitory effect of CLR01 against amyloidogenic proteins is highly specific to abnormal self-assembly of amyloidogenic proteins with no disruption of normal mammalian biologic processes at the doses needed for inhibition. Therapeutic effects of CLR01 have been demonstrated in animal models of proteinopathies, lysosomal-storage diseases, and spinal-cord injury. Here we review the activity and mechanisms of action of these intriguing compounds and discuss future research directions.
Significance Statement Molecular tweezers are supramolecular host molecules with broad biological applications, including inhibition of abnormal protein aggregation, facilitation of lysosomal clearance of toxic aggregates, disruption of viral membranes, and interference of biofilm formation by Gram-positive bacteria. This review discusses the molecular and cellular mechanisms of action of the molecular tweezers, including the discovery of distinct mechanisms acting in vitro and in vivo, and the application of these compounds in multiple preclinical disease models.
Footnotes
- Received May 26, 2022.
- Revision received October 14, 2022.
- Accepted October 19, 2022.
This work was supported by National Institutes of Health National Institutes of Environmental Health Sciences [Grant P01-ES016732], National Institutes of Neurologic Disorders and Stroke [Grant P50-NS38367], National Institute of Aging [Grants P50-AG016570, R01-AG050721, and RF1-AG054000], and National Center of Research Resources [Grant UL1-TR000124]; Michael J. Fox Foundation [Grant 10220]; Team Parkinson/Parkinson Alliance, RJG Foundation [Grant 20095024]; Cure Alzheimer’s Fund [Grant 20152631]; RGK Foundation [Grant 20143057]; CurePSP Foundation [Grant 600-6-15], MSA Coalition [Grant 20170367]; University of Michigan Protein Folding Disease Initiative; German Research Foundation under Germany’s Excellence Strategy RESOLV-EXC-2033 [Grant 390677874]; the Collaborative Research Center CRC 1093 Supramolecular Chemistry on Proteins; and the European Union [Horizon 2020 Grant: Fightn Cov].
G.B., T.S., and F.-G.K. are coauthors and coinventors of 2009 International Patent No. PCT/US2010/026419, USA Patent No. 8,791,092, European Patent No. EP2403859 A2. G.B. is a coauthor and coinventor of 2013 US Patent No. 10,918,657 and 2018 International Patent Application No. PCT/US2019/029221, EU application No. 19850534.9, and International Patent Application No. PCT/US2019/029222, EU application No. 19841367.6. G.B., T.S., J.M., and R.M. are coauthors and coinventors of 2018 International Patent PCT/EP2010/000437, US Patent No. US 8481484 B2, European Patent No. EP 2493859 A1.
↵1 H.S.-K. and I.S. contributed equally to this work.
- Copyright © 2023 by The American Society for Pharmacology and Experimental Therapeutics
PharmRev articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|
Log in using your username and password
Purchase access
In this issue
Jump to section
- Article
- Abstract
- I. Introduction
- II. Discovery of Lys-/Arg-selective MTs
- III. Biologic Applications
- IV. Mechanism of Action Against Amyloidogenic Proteins
- V. Drug-like Properties and Toxicology
- VI. Pending Questions and Future Directions
- VII. Conclusion
- Acknowledgments
- Authorship Contributions
- Footnotes
- Abbreviations
- References
- Figures & Data
- Info & Metrics
- eLetters