One of the major goals of my group is to better understand and treat disorders that are linked to aberrant protein folding and assembly. Our research strategy is interdisciplinary, aiming at utilizing self-assembly processes to design new modalities for arresting amyloid formation in different diseases. We also use self-assembly processes to enhance biological activity by inducing multivalency. The main thrust of my group’s research is summarized below.
Drug Discovery, Design, and Delivery Research for Amyloidogenic Diseases. My group seeks to develop a supramolecular-based platform that can be used as a general scaffold for the design and discovery of novel anti-amyloidogenic compounds with potential application in the treatment of various amyloidogenic diseases, such as Alzheimer’s disease, Parkinson’s disease and type II diabetes. Very recent biochemical and biophysical studies have shown that pathogenic amyloids share common structural and functional features despite being composed of different proteins and amino acids. The similarities between the different amyloids are so immense that soluble aggregates of diverse amyloidogenic proteins, such as insulin, islet amyloid polypeptide, and a-synuclein, can cross-react with each other and be equally recognized by polyclonal antibodies raised against prefibrillar assemblies of amyloid b (Ab) peptides, which are responsible for Alzheimer’s disease. Astonishingly, we have recently found that there are great structural and functional similarities between Ab and the self-assembled cyclic D,L-a-peptides, which lead the latter to cross-react with Ab and modulate its aggregation and toxicity. Moreover, we have shown that the self-assembled cyclic D,L-a-peptides may interact also with other pathogenic amyloids, such as a-Syn and insulin, and inhibit their aggregation and toxicity too. We believe that these studies may shed light on the etiology of misfolded proteins and provide additional insights that can be used to tackle poorly understood topics in the field of misfolded protein diseases, such as the infectious nature of the amyloids and their ability to spread from cell-to-cell. These insights may eventually unravel the mechanism by which proteins begin to misfold to form toxic intermediates, and enhance our ability to intervene in such processes.
Leshem, G., Richman, M., Lisniansky, L., Antman-Passig, M., Habashi, M., Gras̈lund, A., Wärmländer, S. K. Rahimipour, S. Photoactive chlorin e6 is a multifunctional modulator of amyloid-β aggregation and toxicity via specific interactions with its histidine residues. Chem. Sci. 2018, 10, 208-217
Belostozky, A.; Richman, M.; Lisniansky, E.; Tovchygrechko, A.; Chill, J. H.; Rahimipour, S. Inhibition of tau-derived hexapeptide aggregation and toxicity by a self-assembled cyclic d,l-alpha-peptide conformational inhibitor. Chem. Commun. 2018, 54, 5980-5983.
Frenkel-Pinter, M., Richman, M., Belostozky, A., Abu-Mokh, A., Gazit, E., Rahimipour, S.*, Segal, D.* Selective inhibition of aggregation and toxicity of a Tau-derived peptide using its glycosylated analogs. Chem. Eur. J. 2016, 22, 5945-5952 (Cover).
Chemerovski-Glikman M., Rozentur-Shkop E., Richman M., Grupi A., Getler A., Cohen H.Y., Shaked H., Wallin C., Wärmländer S.K., Haas E., Gräslund A., Chill J.H., Rahimipour S. Self-assembled cyclic D,L-α-peptides as generic conformational inhibitors of the α-synuclein aggregation and toxicity: in vitro and mechanistic studies. Chem. Eur. J. 2016, 22, 14236-14246.
Wilik, S., Richman, M., Chemerovski, M., Wärmländer, S., Wahlström, A., Gräslund, A., Rahimipour, S. Anti-amyloidogenic self-assembled cyclic D,L-α-peptides: In vitro and mechanistic studies. J. Am. Chem. Soc. 2013,135, 3474-3484.
Chemerovski, M., Belostozky, A., Richman M., Rahimipour, S. Structure-Based Study of Antiamyloidogenic Cyclic D,L-α-Peptides. Tetrahedron, 2014, 70, 7639-7644.
Developing New Chemical Methods to Induce Multivalency – Application in the Field of Amyloidogenic Diseases Research. My group is also involved in developing new chemical methods to induce a multivalency effect, which is frequently used by nature to dramatically increase the bioactivity of ligands with low individual activity. These methods include the development of a new and straightforward sonochemical method to generate nano- and micro-sized particles bearing multiple copies of a bioactive elements covalently attached to their surface. We have used this technology to show that particles expressing multiple copies of the peptide KLVFF can strongly bind Ab, inhibit its aggregation, and reduce its cytotoxicity. We also found that the anti-amyloidogenic activity of these particles is significantly higher than that of an equimolar concentration of soluble KLVFF—most probably because of the multivalent presentation of the KLVFF peptide. We also showed that such surface-modified nanoparticles can dramatically reduce the inflammation associated with Ab. Initial in vivo toxicity experiments on mice and rats suggest that the particles are biocompatible even after intravenous injection of large doses. Bio-distribution and pharmacokinetic studies are now in progress.
Richman, M., Wilk, S., Skirtenko, N., Perelman, A., Rahimipour, S. Surface-Modified Protein Microspheres Capture Amyloid-β and Inhibit its Aggregation and Toxicity. Chem. Eur. J. 2011, 17, 11171-11177 (Cover)
Richman, M., Perelman, A., Gertler A., Rahimipour, S. Effective Targeting of Aβ to Macrophages by Sonochemically Prepared Surface-Modified Protein Microspheres, Biomacromolecules 2013, 14, 110-116.
Richman M. and Rahimipour S. Surface modified proteinaceous spherical particles and uses thereof, PCT/IB2012/054037
Utilizing Multivalency in the Field of Infectious Disease Research. We also used the multivalency effect induced by surface-modified particles to develop new modalities against bacterial and viral infections. In one example, we showed that the multivalent presentation of mannose on the surface of protein particles can cause bacteria that express mannose-binding receptors to tightly bind to the surface of the particles and inducing agglutination, which was used to detect (sense) low number of bacteria in solution. Moreover, we showed that loading the particles with the common antibacterial drug tetracycline significantly enhanced the antibacterial activity of the encapsulated drug. Enhanced drug activity was also observed when the surface of the particles was modified to express multiple copies of mercaptoethane sulfonate to inhibit HSV-1 infection.
Skirtenko, N. Richman, M., Nitzan, Y. Gedanken, A. Rahimipour, S. A facile one-pot sonochemical synthesis of surface-coated mannosyl protein microspheres for detection and killing of bacteria. Chem. Commun. 2011, 47, 12277-12279 (Cover).
Baram-Pinto, D., Shukla, S., Richman, M., Gedanken, A., Rahimipour, S.*, Sarid, R*. Surface-modified protein microspheres as potential antiviral agents. Chem. Commun. 2012, 48, 8359-8361.
Exploring another direction, we utilized mussel adhesive protein mimics (polydopamine) to modify different surfaces with a two-sided adhesive coating. The modified surfaces were then subjected to nucleophilic reactions with various substances to induce different functionalities on the surface. Using this technology, we recently succeeded in covalently modifying a wide variety of substrates (including glass, metals and polymers (polystyrene and polypropylene)) with different antibacterial and anti-fouling agents (including antimicrobial peptides, quaternary amines, and antibacterial enzymes). We demonstrated that the modified surfaces could effectively kill bacteria on contact without leaching of the active substances from these surfaces. Such surfaces are invaluable for a multitude of purposes, including reducing the spread of many infectious diseases.
By combining the above polydopamine chemistry and sonochemistry, my team also succeeded in generating polydopamine nanoparticles that preserve all the characteristics of polydopamine. We utilized the reactivity of the nanoparticles toward different nucleophiles to introduce new functionalities onto the particles’ surfaces. More interestingly, we showed for the first time that the presence of Cu or Ag ions during sonochemical irradiation generates particles that exhibit potent antibacterial and antifouling activity, without inducing any toxicity to mammalian cells. These particles could potentially be painted onto a wide range of surfaces to inhibit bacterial growth.
Shalev, T., Gopin, A., Bauer, M., Stark, R.W., Rahimipour, S.Non-leaching antimicrobial surfaces through polydopamine bio-inspired coating of quaternary ammonium salts or an ultrashort antimicrobial lipopeptide. J. Mater. Chem. 2012, 22, 2026-2032
Yeroslavsky, G., Richman, M., Dawidowicz, L. Rahimipour, S. Sonochemically produced polydopamine nanocapsules with selective antimicrobial activity. Chem. Commun. 2013, 49, 5721-5723 (Cover).
Yeroslavsky G., Girshevitz O., Foster-Frey J., Donovan D.M., Rahimipour S. Antibacterial and antibiofilm surfaces through polydopamine-assisted immobilization of lysostaphin as an antibacterial enzyme. Langmuir 2015, 31, 1064-1073.
Yeroslavsky G., Lavi R., Alishaev A., Rahimipour S. Sonochemically-produced metal-containing polydopamine nanoparticles and their antibacterial and antibiofilm activity. Langmuir. 2016, 32, 5201-5012.
Yeroslavsky, G. and Rahimipour S. Polydopamine nanocapsules and uses thereof. Provisional Patent Application 2012
Utilizing Multivalency and Supramolecular Chemistry in the Field of Inflammatory Disease Research: Type II Diabetes and Multiple Sclerosis. Various aspects of oxidative cellular stress are associated with the pathogenesis of several devastating human diseases, including diabetes, Alzheimer’s disease, Parkinson’s disease, and multiple sclerosis. It is well known that the generation of reactive oxygen species (ROS) in abnormal amounts or an impairment of the cells’ anti-oxidative protective systems can lead to cellular and tissue damage.
We demonstrated that the multivalent presentation of histidine residues induced by the abiotic self-assembly of cyclic D,L-a-peptides can lead to the generation of multifunctional agents that catalytically decompose intracellular ROS and induce cell protection. In particular, we showed that treatment of muscle cells with such permeable His-rich cyclic peptides protects the cells against the oxidative stress that is induced by hyperglycemic conditions and increases the uptake of glucose from the periphery by increasing the translocation of GLUT1 and GLUT4. In neuronal cells, we were able to show that these peptides exhibit potent anti-inflammatory, anti-oxidant, and anti-excitotoxic activity, and protect the neurons against axonal damage. In a pilot study carried out in collaboration with Teva Pharmaceutical Industries Ltd., we were able to demonstrate that the discovered cyclic peptides exhibit potent neuroprotecting activity in an animal model of multiple sclerosis (experimental autoimmune encephalomyelitis) and significantly ameliorate the related symptoms.
Shapira, R., Rudnick, S., Daniel, B., Viskind, O., Aisha, V., Richman, M., Perelman, A., Chill, J. H., Gruzman, A., Rahimipour, S. Multifunctional cyclic D,L-α-peptide architectures stimulate non-insulin dependent glucose uptake in skeletal muscle cells and protect them against oxidative stress, J. Med. Chem. 2013, 56, 6709-6718.
Shapiro R. and Rahimipour S. Neuroprotective cyclic peptides, Provisional Patent Application, 2012.