Research
Amyloid Aggregation Modulators
Several degenerative diseases are characterized by self-assembly of proteins into aggregates termed amyloids, which share several physicochemical features: a fibrillar morphology, a predominantly β-sheet secondary structure, insolubility in common solvents and detergents, and protease resistance. These so-called amyloid diseases include Alzheimer’s disease, Huntington's disease, Parkinson's disease, prion diseases (Creutzfeldt-Jakob disease in humans and ‘mad cow disease’ in cattle), and type II diabetes.
A major research focus of the lab is on developing peptide- and small-molecule based amyloid inhibitors. Current efforts include designing cell-penetrating peptide (CPP) inhibitors of the aggregation and cytotoxicity of the amyloid-β (Aβ) peptide, which is implicated in Alzheimer’s disease (AD). CPPs are short peptides that enter cells with high efficiency in vitro and in vivo, and can cross the blood-brain barrier. Thus, these CPPs combine the attractive intrinsic properties of peptides (e.g. high target specificity and selectivity, biocompatibility, biodegradability and ease and low cost of production) with potent therapeutic effects (i.e. inhibition of Aβ amyloid formation and the associated neurotoxicity) and highly efficient delivery (to target tissue, cells and subcellular organelles).
Along with our collaborators, we are also synthesizing α-helix mimetic inhibitors of the pathogenic self-assembly of a range of amyloid proteins. α-helix mimetics are structured scaffolds that imitate the topography of the most commonly occurring protein secondary structure, serving as effective antagonists of protein–protein interactions (PPIs) at the interaction interface. The appeal of α-helix mimetics stems from the fact that their side-chain residues can be conveniently manipulated to target specific disease-related PPIs.
Cancer Therapeutics
We are interested in developing tumor-specific therapeutics. These include small molecules, peptides and proteins. An example is our protein mimetic-based approach to abrogate cancer-associated mutant p53 aggregation and restore tumor suppressor function.
Dubbed the ‘guardian of the genome’, p53 is a tumor suppressor protein that is activated under cellular stresses, including DNA damage, oncogene activation, oxidative stress or hypoxia. Upon activation, p53 triggers DNA damage repair, cell cycle arrest, senescence, apoptosis or autophagy, all of which are directed towards suppression of neoplastic transformation and inhibition of tumor progression. Crucially, p53 missense mutations occur in over half of all human cancers, and many of these mutations induce self-assembly of p53 into inactive cytosolic amyloid-like aggregates. Screening a library of synthetic protein mimetics, we identified one, ADH-6, that potently abrogates dissociates mutant p53 aggregates and restores the protein’s transcriptional activity, leading to cell cycle arrest and apoptosis. Notably, ADH-6 treatment effectively shrinks xenografts harboring mutant p53, while exhibiting no toxicity to healthy tissue, thereby substantially prolonging survival.
Another example is our CPP derived from the mitochondrial membrane-binding N-terminal domain of hexokinase II (HKII). Overexpression of mitochondria-bound HKII in cancer cells plays a paramount role in their metabolic reprogramming and protects them against apoptosis, thereby facilitating their growth and proliferation. The HKII-derived peptide, pHK-PAS, is readily taken up by cancer cells where it effectively disrupts the mitochondria-HKII association, leading to mitochondrial dysfunction and finally apoptosis. Significantly, pHK-PAS treatment of non-cancerous cells results in negligible cytotoxicity. Our results demonstrate the potential of the pHK-PAS CPP as a novel cancer therapeutic strategy.
Palanikumar, L., Al-Hosani, S., Kalmouni, M., Saleh, H. & Magzoub, M.* (2020) Hexokinase II-derived cell-penetrating peptide mediates delivery of microRNA mimic for cancer-selective cytotoxicity. Biochemistry 59, 2259–2273.
Woldetsadik, A.D., Vogel, M.C., Rabeh, W.M. & Magzoub, M.* (2017) Hexokinase II-derived cell-penetrating peptide targets mitochondria and triggers apoptosis in cancer cells. FASEB J. 31, 2168-2184.
DRUG DELIVERY NANOPLATFORMS
Cancer nanomedicine has the potential to overcome the intrinsic limitations of conventional chemotherapeutics, such as poor solubility, short in vivo circulation time, toxicity to healthy tissue, drug resistance and tumor recurrence. However, the practical application of nanocarriers is hampered by several issues, including poor circulation stability, inadequate accumulation in target tumor tissue and inefficient uptake and/or intracellular trafficking in target cancer cells.
To address these issues, we have utilized a simple and robust approach to prepare hybrid nanoparticles (NPs) that consist of a polylactic-co-glycolic acid (PLGA) core ‘wrapped’ with a cross-linked bovine serum albumin (BSA) shell that is functionalized with the tumor targeting acidity-triggered rational membrane (ATRAM) peptide. The ATRAM-BSA-PLGA NPs combine the following properties: (i) low cost and ease of preparation; (ii) high drug encapsulation stability; (iii) biocompatibility and biodegradability; (iv) minimal interactions with serum proteins and macrophages; (v) increased in vivo circulation half-life of the chemotherapeutic cargo; (vi) efficient and specific internalization into cancer cells within an acidic environment such as that of solid tumors; (vii) triggered cytosolic release of the chemotherapeutic cargo in cancer cells; and (viii) effective targeting of tumors, leading to a substantial reduction in tumor volume and mass and prolonged survival.
Non-invasive light-based therapies, such as photodynamic therapy (PDT) and photothermal therapy (PTT), have recently garnered considerable interest as potentially safe and effective alternatives to the traditional cancer treatments of chemotherapy, radiotherapy and surgery. PDT uses laser irradiation to activate a photosensitizer (PS) that subsequently generates cytotoxic reactive oxygen species (ROS), through a series of photochemical reactions, to induce apoptosis in cancer cells, while in PTT a photothermal agent (PTA) converts absorbed light into heat and the resulting hyperthermia leads to the partial or complete ablation of tumor tissue. However, poor solubility, low stability, and lack of tumor specificity of many common PSs and PTAs have hindered the clinical application of PDT and PTT.
Recently, we have engineered multifunctional nanospheres that overcome the aforementioned challenges. These biocompatible and biodegradable core-shell nanospheres consist of a lanthanide- and PTA-doped upconversion core within a PS-loaded mesoporous silica shell. The shell is wrapped with a lipid/PEG bilayer that is functionalized with ATRAM. The ATRAM-functionalized, lipid/PEG-coated upconversion mesoporous silica nanospheres (ALUMSNs) enable tumor detection via magnetic resonance, fluorescence and thermal imaging. The ALUMSNs additionally facilitate NIR laser light-induced PDT and PTT to substantially shrink tumors, with no detectable adverse effects to healthy tissue.
Illustration by Khulood Alawadi (Lecturer of Engineering, NYUAD)
Funding Sources
Phone: +971 2 628 4760
Fax: +971 2 659 0791
Magzoub Lab
Experimental Research Building (ERB)
NYU Abu Dhabi
Saadiyat Island Campus
P.O. Box 129188
Abu Dhabi, United Arab Emirates
