RT Journal Article
SR Electronic
T1 Molecular Tweezers: Supramolecular Hosts with Broad-Spectrum Biological Applications
JF Pharmacological Reviews
JO Pharmacol Rev
FD American Society for Pharmacology and Experimental Therapeutics
SP 263
OP 308
DO 10.1124/pharmrev.122.000654
VO 75
IS 2
A1 Shahpasand-Kroner, Hedieh
A1 Siddique, Ibrar
A1 Malik, Ravinder
A1 Linares, Gabriel R.
A1 Ivanova, Magdalena I.
A1 Ichida, Justin
A1 Weil, Tatjana
A1 Münch, Jan
A1 Sanchez-Garcia, Elsa
A1 Klärner, Frank-Gerrit
A1 Schrader, Thomas
A1 Bitan, Gal
A2 Khoshbouei, Habibeh
YR 2023
UL http://pharmrev.aspetjournals.org/content/75/2/263.abstract
AB 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.