CLR01 / UCLA - LARVOL DELTA

Allosteric Modulation of Pathological Ataxin-3 Aggregation: A Path to Spinocerebellar Ataxia Type-3 Therapies. (PubMed, bioRxiv) - "This study provides critical insights into Atx3 self-assembly, revealing a novel allosteric site for designing CLR01-inspired therapies targeting pathological aggregation pathways while sparing essential functional sites. These findings emphasize that targeting allosteric sites in amyloid-forming proteins may offer unique opportunities to develop safe therapeutic strategies for various protein misfolding disorders."

Journal • Ataxia • CNS Disorders • Movement Disorders • Proteinopathy • Targeted Protein Degradation • ATXN3 • UBB

Anti-amyloid treatment is broadly effective in neuronopathic mucopolysaccharidoses and synergizes with gene therapy in MPS-IIIA. (PubMed, Mol Ther) - "Moreover, we demonstrate that CLR01 is effective therapeutically in mouse models of other forms of neuronopathic MPS, MPS-I and MPS-IIIC. These strongly support developing MTs as an effective treatment option for neuronopathic MPSs, both on their own and in combination with gene therapy, to improve therapeutic efficacy and translation into clinical application."

Gene therapy • Journal • CNS Disorders • Gene Therapies • Lysosomal Storage Diseases

EXPLORING ATAXIN-3 PATHOGENIC AGGREGATION PATHWAYS VIA SUPRAMOLECULAR INHIBITION: IMPLICATIONS FOR THERAPEUTIC DEVELOPMENT (ADPD 2024) - "CLR01 has the potential to mitigate the harmful effects of Atx3 aggregation in SCA3 and can contribute to the development of molecules that specifically target neurotoxic pathways."

Ataxia • Movement Disorders • ATXN3

Characterization of Molecular Tweezer Binding on α-Synuclein with Native Top-Down Mass Spectrometry and Ion Mobility-Mass Spectrometry Reveals a Mechanism for Aggregation Inhibition. (PubMed, J Am Soc Mass Spectrom) - "These data suggest that when multiple CLR01 molecules bind, the N-terminus of α-synuclein shifts toward a more compact state. This compaction suggests a mechanism for CLR01 halting the formation of oligomers and fibrils involved in many neurodegenerative diseases."

Journal • CNS Disorders • Movement Disorders • Parkinson's Disease

Molecular tweezers - supramolecular hosts with broad-spectrum biological applications. (PubMed, Pharmacol Rev) - "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...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 pre-clinical disease models."

Journal • Alzheimer's Disease • CNS Disorders • Human Immunodeficiency Virus • Infectious Disease • Lysosomal Storage Diseases • Metabolic Disorders • Movement Disorders • Novel Coronavirus Disease • Orthopedics • Parkinson's Disease • Proteinopathy • Rare Diseases • Respiratory Diseases

Advanced Molecular Tweezers with Lipid Anchors against SARS-CoV-2 and Other Respiratory Viruses. (PubMed, JACS Au) - "Here, we show that first-generation tweezers, CLR01 and CLR05, disrupt the SARS-CoV-2 envelope and abrogate viral infectivity...Moreover, inhibitory activity of advanced tweezers against respiratory syncytial virus and SARS-CoV-2 was confirmed in mice. Thus, potentiated tweezers are broad-spectrum antiviral agents with great prospects for clinical development to combat highly pathogenic viruses."

Journal • Infectious Disease • Influenza • Novel Coronavirus Disease • Respiratory Diseases • Respiratory Syncytial Virus Infections

Superoxide dismutase 1 folding stability as a target for molecular tweezers in SOD1-related amyotrophic lateral sclerosis. (PubMed, Chembiochem) - "As a supramolecular ligand that binds to lysine and arginine residues, the molecular tweezer CLR01 was found to modify the aggregation pathway of disease-relevant proteins in vitro and in vivo with beneficial effects on toxicity...Molecular dynamics simulations and binding free energy calculations as well as native mass spectrometry and mutational studies allowed us to identify K61 and K92 as binding sites for the tweezers to mediate the stability increase. The data suggest that the modulation of SOD1 conformational stability is a promising target for future developments of supramolecular ligands against neurodegenerative diseases."

Journal • Alzheimer's Disease • Amyotrophic Lateral Sclerosis • CNS Disorders • Huntington's Disease • Movement Disorders • Parkinson's Disease • SOD1

Exploring the Binding Mechanism of a Supramolecular Tweezer CLR01 to 14-3-3σ Protein via Well-Tempered Metadynamics. (PubMed, Front Chem) - "This could be helpful for the development of new inhibitors based on tweezers with more functions against 14-3-3 proteins via modifications of CLR01. We also believe that the proposed computational strategies can be extended to understand the binding mechanism of multi-binding sites proteins with supramolecules and will, thus, be useful toward drug design."

Journal

Three-repeat and four-repeat Tau isoforms form different oligomers. (PubMed, Protein Sci) - "We also tested whether known inhibitors of tau aggregation affect its oligomerization using three small molecules representing different classes of tau aggregation inhibitors, Methylene Blue (MB), the molecular tweezer CLR01, and the all-D peptide TLKIVW, for their ability to inhibit or modulate the oligomerization of the six tau isoforms...Unlike their reported inhibitory effect on tau fibrillation, the inhibitors had little or no effect on the initial oligomerization. Our study provides novel insight into the primary-quaternary structure relationship of human tau and suggests that 3R-tau oligomers may be an important target for future development of compounds targeting pathological tau assemblies."

Journal

The Molecular Tweezer CLR01 Inhibits Antibody-Resistant Cell-to-Cell Spread of Human Cytomegalovirus. (PubMed, Viruses) - "Therefore, it would be therapeutically interesting to target this mode of spread in order to treat severe HCMV infections and to prevent dissemination of virus within the infected host. The molecular tweezer CLR01 exhibits broad-spectrum antiviral activity against a number of enveloped viruses and efficiently blocks antibody-resistant cell-to-cell spread of HCMV, thus representing a novel class of small molecules with promising antiviral activity."

Journal • Cytomegalovirus Infection • Herpes Simplex • Infectious Disease

Lysine-selective molecular tweezers are cell penetrant and concentrate in lysosomes. (PubMed, Commun Biol) - "The main impediment to answering these questions has been the low intrinsic fluorescence of the main compound tested to date, called CLR01...Moreover, by visualizing colocalization of molecular tweezers, lysosomes, and tau aggregates we show that lysosomes likely are the main site for the intracellular anti-amyloid activity of molecular tweezers. These findings have important implications for the mechanism of action of molecular tweezers in vivo, explaining how administration of low doses of the compounds achieves high effective concentrations where they are needed, and supporting the development of these compounds as drugs for currently cureless proteinopathies."

Journal • Infectious Disease • Proteinopathy

[VIRTUAL] Experimental Therapies for Rare Movement Disorders – MSA (EAN 2021) - P1, P2 | "In this regard, enhancing the clearance of α-synuclein via autophagy (transcription factor EB) or direct proteolysis (neurosin), inhibiting its aggregation (anle 138b and CLR01) or post-translational truncation (belnacasan), as well as active (Affitope PD01A) and passive immunotherapy (CD5-D5) have demonstrated beneficial effects on motor behavior, α-synuclein burden and other neuropathological readouts in transgenic MSA mice...These preclinical results have motivated the conduction of a phase I trial to evaluate the safety and tolerability of repeated administrations of specific active immunotherapy against α-synuclein with Affitope PD01A and PD03A (NCT02270489)...In this regard, a phase I trial to assess the safety and tolerability of anle138b in healthy volunteers is currently ongoing (NCT04208152). Additionally, a small phase II trial with exenatide (NCT04431713), an approved antidiabetic, is ongoing."

Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Dementia • Lewy Body Disease • Movement Disorders • Multiple System Atrophy • Parkinson's Disease • Solid Tumor • Targeted Protein Degradation • CD5 • TFEB • TLR4

Inhibition of Staphylococcus aureus biofilm-forming functional amyloid by molecular tweezers. (PubMed, Cell Chem Biol) - "In comparison, different peptide binding occurs in the case of CLR05, a tweezer containing methylenecarboxylate units, which exhibits lower affinity for the lysine residues yet disrupts S. aureus biofilm more strongly than CLR01. Our study points to a possible role for molecular tweezers as potent biofilm inhibitors and antibacterial agents, particularly against untreatable biofilm-forming and PSM-producing bacteria, such as methicillin-resistant S. aureus."

Journal

Prospects of ultraviolet resonance Raman spectroscopy in supramolecular chemistry on proteins. (PubMed, Spectrochim Acta A Mol Biomol Spectrosc) - "We focus on selected artificial ligands which were rationally designed as selective carboxylate binders (guanidiniocarbonyl pyrrole, GCP, and guanidiniocarbonyl indole, GCI) and selective lysine binder (molecular tweezer, CLR01), respectively, via a combination of non-covalent interactions involving electrostatics, hydrogen bonding, and hydrophobic effects/van der Waals forces...We then propose solutions to overcome these limitations for transforming UVRR spectroscopy into a generic tool in supramolecular chemistry on proteins, with an emphasis on mono- and multivalent GCP- and GCI-based ligands. Finally, we outline specific cases of supramolecular ligands such as molecular tweezers where alternative approaches such as laser-based mid-IR spectroscopy are required since UVRR can intrinsically not provide the required molecular information."

Journal

Disaggregation mechanism of prion amyloid for tweezer inhibitor. (PubMed, Int J Biol Macromol) - "Moreover, the CLR01 remodelled the pentamer Prion into a compact structure which might be the resistant conformation for further oligomerization. Our work will contribute to better understand the interaction and deterioration mechanism of molecular tweezer for prions and similar amyloids, and offer significant insights into therapeutic development for Amyloidosis treatment."

Journal • Amyloidosis

The molecular tweezer CLR01 improves behavioral deficits and reduces tau pathology in P301S-tau transgenic mice. (PubMed, Alzheimers Res Ther) - "The findings suggest that CLR01 is a particularly attractive candidate for the treatment of AD because it targets simultaneously the two major pathogenic proteins instigating and propagating the disease, amyloid β-protein (Aβ), and tau, respectively. In addition, our study suggests that CLR01 can be used for the treatment of other tauopathies in the absence of amyloid pathology."

Journal • Alzheimer's Disease • CNS Disorders • Mood Disorders • Psychiatry

Impact of K16A and K28A mutation on the structure and dynamics of amyloid-β peptide in Alzheimer's disease: Key insights from molecular dynamics simulations. (PubMed, J Biomol Struct Dyn) - "The recent studies highlighted that lysine residues (K16 and K28) play a critical role in the Aβ self-assembly and are the target of entities like molecular tweezer, CLR01...The short-range tertiary contacts between central hydrophobic core and C-terminal region were relatively reduced in K16A and K28A as compare to wild type (wt) Aβ. The mechanistic insights from the study will be beneficial for the design and development of novel inhibitors that will bind and block the interactions, mediated by lysine residues specifically, critical for the Aβ self-assembly in Alzheimer disease."

Journal • Alzheimer's Disease • CNS Disorders

Supramolecular Mechanism of Viral Envelope Disruption by Molecular Tweezers. (PubMed, J Am Chem Soc) - "The most potent ester modifications harbored unbranched C4 units, which engendered tweezers that were approximately one order of magnitude more effective than CLR01 and nontoxic. Thus, we establish the mechanistic basis of viral envelope disruption by specific tweezers and establish a new class of potential broad-spectrum antivirals with enhanced activity."

Journal • Human Immunodeficiency Virus • Infectious Disease • Novel Coronavirus Disease

CLR01 protects dopaminergic neurons in vitro and in mouse models of Parkinson's disease. (PubMed, Nat Commun) - "Finally, CLR01 reduced alpha-synuclein-associated pathology in mice injected with alpha-synuclein aggregates into the striatum or substantia nigra. Taken together, these results highlight CLR01 as a disease-modifying therapy for PD and support further clinical investigation."

Journal • Preclinical • CNS Disorders • Movement Disorders • Parkinson's Disease

Different inhibitors of Aβ42-induced toxicity have distinct metal-ion dependency. (PubMed, ACS Chem Neurosci) - "In agreement with these results, CLR01 inhibited β-sheet and fibril formation in Aβ42-Zn2+ complexes. Our data suggest that for development of efficient therapeutic agents, inhibitors of Aβ self-assembly and toxicity should be examined in the presence of relevant metal ions, and that molecular tweezers may be particularly attractive candidates for therapy development."

Journal • Alzheimer's Disease • CNS Disorders

The molecular tweezer CLR01 reduces aggregated, pathologic, and seeding-competent α-synuclein in experimental multiple system atrophy. (PubMed, Biochim Biophys Acta Mol Basis Dis) - "To our knowledge, this is the first demonstration of an agent that reduces formation of putative high-molecular-weight oligomers and seeding-competent α-syn in a mouse model of MSA, supporting the view that these species are key to the neurodegenerative process and its cell-to-cell progression in MSA. Our study suggests that CLR01 is an attractive therapeutic candidate for disease modification in MSA and related synucleinopathies, supporting further preclinical development."

Journal • CNS Disorders • Mood Disorders • Movement Disorders • Multiple System Atrophy • Solid Tumor

Computational investigations on the dynamic binding effect of molecular tweezer CLR01 towards intrinsically disordered HIV-1 Nef. (PubMed, Biotechnol Appl Biochem) - "The docking results were further validated from the molecular dynamics simulation studies confirming the conformational stability of Nef upon tweezer binding. These findings provide useful insights into the development of potent inhibitors for targeting Nef protein functions."

Journal • Gene Therapies • Infectious Disease