Amino Acids, Peptides, and Proteins Commons^™

Study Of Potential Drug For Alzheimer’S Disease: Small Organic Molecules, 1,5-Dhn And Tmpyp Inhibit Amyloid-Β Peptide Aggregation And Quench Hydroxyl Radicals, Matthew Murphy

Undergraduate Research Conference

Alzheimer disease (AD) is recognized as the six leading cause of the death in the United States. As of now, there is no cure for this fatal disease. The current treatment methods can only temporarily slow the worsening of symptoms. Research data suggested that an excess generation of hydroxyl radical in the brain causing the aggregation of Amyloid-β (Aβ) peptide which is considered to be responsible for Alzheimer's disease. Thus, there is a pressing need to find a suitable drug which can quench hydroxyl radicals effectively and stop or slow down the formation of aggregation of Aβ peptide. The primary …

The Mechanism Of Β-N-Methylamino-L-Alanine Inhibition Of Trna Aminoacylation And Its Impact On Misincorporation, Nien-Ching Han, Tammy J. Bullwinkle, Kaeli F. Loeb, Kym F. Faull, Kyle Mohler, Jesse Rinehart, Michael Ibba

Biology, Chemistry, and Environmental Sciences Faculty Articles and Research

β-N-methylamino-l-alanine (BMAA) is a nonproteinogenic amino acid that has been associated with neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS) and Alzheimer's disease (AD). BMAA has been found in human protein extracts; however, the mechanism by which it enters the proteome is still unclear. It has been suggested that BMAA is misincorporated at serine codons during protein synthesis, but direct evidence of its cotranslational incorporation is currently lacking. Here, using LC-MS–purified BMAA and several biochemical assays, we sought to determine whether any aminoacyl-tRNA synthetase (aaRS) utilizes BMAA as a substrate for aminoacylation. Despite BMAA's previously predicted misincorporation at serine …

[(Wr)8Wkβa]-Doxorubicin Conjugate: A Delivery System To Overcome Multi-Drug Resistance Against Doxorubicin, Khalid Zoghebi, Hamidreza Montazeri Aliabadi, Rakesh Kumar Tiwari, Keykavous Parang

Pharmacy Faculty Articles and Research

Doxorubicin (Dox) is an anthracycline chemotherapeutic agent used to treat breast, leukemia, and lymphoma malignancies. However, cardiotoxicity and inherent acquired resistance are major drawbacks, limiting its clinical application. We have previously shown that cyclic peptide [WR]₉ containing alternate tryptophan (W) and arginine (R) residues acts as an efficient molecular transporter. An amphiphilic cyclic peptide containing a lysine (K) residue and alternative W and R was conjugated through a free side chain amino group with Dox via a glutarate linker to afford [(WR)₈WKβA]-Dox conjugate. Antiproliferative assays were performed in different cancer cell lines using the conjugate and the …

A Global Review On Short Peptides: Frontiers And Perspectives, Vasso Apostolopoulos, Joanna Bojarska, Tsun-Thai Chai, Sherif Elnagdy, Krzysztof Kaczmarek, John Matsoukas, Roger New, Keykavous Parang, Octavio Paredes Lopez, Hamideh Parhiz, Conrad O. Perera, Monica Pickholz, Milan Remko, Michele Saviano, Mariusz Skwarczynski, Yefeng Tang, Wojciech M. Wolf, Taku Yoshiya, Janusz Zabrocki, Piotr Zielenkiewicz, Maha Alkhazindar, Vanessa Barriga, Konstantinos Kelaidonis, Elham Mousavinezhad Sarasia, Istvan Toth

Pharmacy Faculty Articles and Research

Peptides are fragments of proteins that carry out biological functions. They act as signaling entities via all domains of life and interfere with protein-protein interactions, which are indispensable in bio-processes. Short peptides include fundamental molecular information for a prelude to the symphony of life. They have aroused considerable interest due to their unique features and great promise in innovative bio-therapies. This work focusing on the current state-of-the-art short peptide-based therapeutical developments is the first global review written by researchers from all continents, as a celebration of 100 years of peptide therapeutics since the commencement of insulin therapy in the 1920s. …

Structural Characterization And In Vitro Antiproliferative Activity Of Non-Specific Lipid Transfer Protein 1 (Nsltp1) From Fennel (Foeniculum Vulgare) Seeds, Mekdes Megeressa

Pharmaceutical Sciences (PhD) Dissertations

Non-specific lipid transfer proteins (nsLTPs) are cationic proteins involved in intracellular lipid shuttling, in growth and reproduction, as well as in defense against pathogenic microbes. Even though the primary and spatial structures of some nsLTPs from different plants indicate their similar features, they exhibit distinct lipid-binding specificities signifying their various biological roles that dictate further structural study. The present study determined the complete amino acid sequence, in silico 3D structure modeling, and in vitro antiproliferative activity of nsLTP1 from fennel (Foeniculum vulgare) seeds.

Fennel is a member of the family Umbelliferae (Apiaceae) native to southern Europe and the …

Amphiphilic Cell-Penetrating Peptides Containing Natural And Unnatural Amino Acids As Drug Delivery Tools And Antimicrobial Agents, David Salehi

Pharmaceutical Sciences (MS) Theses

Cell-penetrating peptides containing arginine as positively charged residues and tryptophan or diphenylalanine as hydrophobic residues were synthesized. The synthesis was accomplished through the Fmoc solid-phase peptide synthesis in the presence of HBTU and DIPEA. The side-chain protected linear peptides were cleaved from the resin and cyclized in the presence of DIC and HOAt in the solution phase overnight. MALDI-TOF mass spectrometry was used to characterize the peptides.

The cytotoxicity of the synthesized peptides was determined in CCRF-CEM (human, lymphoblast peripheral blood), and HEK-293 (human, embryonic epithelial kidney healthy) cells using the MTS assay. A concentration of 10 µM was found …

Targeting Calcium Homeostasis For The Treatment Of Multiple Myeloma, Osama M. Elzamzamy

Graduate Theses, Dissertations, and Problem Reports (ETD)

Multiple myeloma (MM) is a hematological malignancy characterized by the neoplastic proliferation of the plasma cells. MM is a relatively rare cancer that accounts for about 1.8% of all cancers and is the second most common hematologic malignancies, and despite the advancement from untreatable to treatable malignancy, it is yet incurable. Calcium ions (Ca²⁺) play an important role as second messengers in regulating a plethora of physiological and pathological processes, hence cytoplasmic Ca²⁺ is tightly regulated with strict spatial and temporal control to initiate, maintain, and terminate appropriate signaling pathways and phenotypes including cellular proliferation, cell cycle …

Evaluation Of Albumin 5% Prescribing Patterns In Adult Hospitalized Patients, Robyn Feldman, Nicole Tadros, Heidi Clarke, Erika Dittmar

All Publications

No abstract provided.

Evaluating The Association Between Vasopressin Use And In-Hospital Mortality In Patients With Septic Shock, Michael Pasqualicchio, Heidi Clarke, Jonathan Kline, Payal Patel

All Publications

No abstract provided.

Structural Characterization And In Vitro Lipid Binding Studies Of Non-Specific Lipid Transfer Protein 1 (Nsltp1) From Fennel (Foeniculum Vulgare) Seeds, Mekdes Megeressa, Bushra Siraj, Shamshad Zarina, Aftab Ahmed

Pharmacy Faculty Articles and Research

Non-specific lipid transfer proteins (nsLTPs) are cationic proteins involved in intracellular lipid shuttling in growth and reproduction, as well as in defense against pathogenic microbes. Even though the primary and spatial structures of some nsLTPs from different plants indicate their similar features, they exhibit distinct lipid-binding specificities signifying their various biological roles that dictate further structural study. The present study determined the complete amino acid sequence, in silico 3D structure modeling, and the antiproliferative activity of nsLTP1 from fennel (Foeniculum vulgare) seeds. Fennel is a member of the family Umbelliferae (Apiaceae) native to southern Europe and the Mediterranean …

An Update Of The Virion Proteome Of Kaposi Sarcoma-Associated Herpesvirus, Ramina Nabiee, Basir Syed, Jesus Ramirez Castano, Rukhsana Lalani, Jennifer Totonchy

Pharmacy Faculty Articles and Research

The virion proteins of Kaposi sarcoma-associated herpesvirus (KSHV) were initially characterized in 2005 in two separate studies that combined the detection of 24 viral proteins and a few cellular components via LC-MS/MS or MALDI-TOF. Despite considerable advances in the sensitivity and specificity of mass spectrometry instrumentation in recent years, leading to significantly higher yields in detections, the KSHV virion proteome has not been revisited. In this study, we have re-examined the protein composition of purified KSHV virions via ultra-high resolution Qq time-of-flight mass spectrometry (UHR-QqTOF). Our results confirm the detection of all previously reported virion proteins, in addition to 17 …

Cytokine-Targeted Therapeutics For Kshv-Associated Disease, Nedaa Alomari, Jennifer Totonchy

Pharmacy Faculty Articles and Research

Kaposi’s sarcoma-associated herpesvirus (KSHV) also known as human herpesvirus 8 (HHV-8), is linked to several human malignancies including Kaposi sarcoma (KS), primary effusion lymphoma (PEL), multicentric Castleman’s disease (MCD) and recently KSHV inflammatory cytokine syndrome (KICS). As with other diseases that have a significant inflammatory component, current therapy for KSHV-associated disease is associated with significant off-target effects. However, recent advances in our understanding of the pathogenesis of KSHV have produced new insight into the use of cytokines as potential therapeutic targets. Better understanding of the role of cytokines during KSHV infection and tumorigenesis may lead to new preventive or therapeutic …

Click-Free Synthesis Of A Multivalent Tricyclic Peptide As A Molecular Transporter, Sumit Kumar, Dindyal Mandal, Shaima Ahmed El-Mowafi, Saghar Mozaffari, Rakesh Kumar Tiwari, Keykavous Parang

Pharmacy Faculty Articles and Research

The cellular delivery of cell-impermeable and water-insoluble molecules remains an ongoing challenge to overcome. Previously, we reported amphipathic cyclic peptides c[WR]₄ and c[WR]₅ consisting of alternate arginine and tryptophan residues as nuclear-targeting molecular transporters. These peptides contain an optimal balance of positive charge and hydrophobicity, which is required for interactions with the phospholipid bilayer to facilitate their application as a drug delivery system. To further optimize them, we synthesized and evaluated a multivalent tricyclic peptide as an efficient molecular transporter. The monomeric cyclic peptide building blocks were synthesized using Fmoc/tBu solid-phase chemistry and cyclization in the …

Effect Of High Glucose On Ocular Surface Epithelial Cell Barrier And Tight Junction Proteins, Saleh M. Alfuraih, Ashley Barbarino, Christopher Ross, Kiumars Shamloo, Vishal Jhanji, Miao Zhang, Ajay Sharma

Pharmacy Faculty Articles and Research

PURPOSE. Patients with diabetes mellitus are reported to have ocular surface defects, impaired ocular surface barrier function, and a higher incidence of corneal and conjunctival infections. Tight junctions are critical for ocular surface barrier function. The present study was designed to investigate the effect of high glucose exposure on human corneal and conjunctival epithelial cell barrier function and tight junction proteins.

METHODS. Human corneal and conjunctival epithelial cells were exposed to 15 mM and 30 mM glucose for 24 and 72 hours. The barrier function was measured using transepithelial electrical resistance (TEER). The cell migration was quantified using scratch assay. …

Cyclic Peptide-Gadolinium Nanoparticles For Enhanced Intracellular Delivery, Amir Nasrolahi Shirazi, Shang Eun Park, Shirin Rad, Luiza Baloyan, Dindyal Mandal, Muhammad Imran Sajid, Ryley Hall, Sandeep Lohan, Khalid Zoghebi, Keykavous Parang, Rakesh Tiwari

Pharmacy Faculty Articles and Research

A cyclic peptide containing one cysteine and five alternating tryptophan and arginine amino acids [(WR)₅C] was synthesized using Fmoc/tBu solid-phase methodology. The ability of the synthesized cyclic peptide to produce gadolinium nanoparticles through an in situ one-pot mixing of an aqueous solution of GdCl₃ with [(WR)₅C] peptide solution was evaluated. Transmission electron microscopy showed the formed peptide-Gd nanoparticles in star-shape morphology with a size of ~250 nm. Flow cytometry investigation showed that the cellular uptake of a cell-impermeable fluorescence-labeled phosphopeptide (F′-GpYEEI, where F′ = fluorescein) was approximately six times higher in the presence of [(WR) …

Cancer-Targeting Immunostimulatory Peptides As An Immunotherapeutic Approach To Cancer, Rachel Montel

Seton Hall University Dissertations and Theses (ETDs)

This dissertation reports the synthesis and biological applications of bifunctional trimeric peptides with B7H6-derived NKp30 binding motifs that serve to activate an immunocytotoxic response in natural killer cells and a GRP78-binding motif that can target tumors that express surface GRP78. In this manner the cancer-targeting immunostimulatory peptides are anticipated to directly bind and activate effector NK92-MI cells while also recognizing and binding to target A549 tumor cells to facilitate NK cell-dependent immunocytotoxicity of the targeted tumors. The NKp30 binding peptide motifs are derived from the tumor associated B7H6 antigen that is often downregulated or shed from the surface of tumors …

Cyclic Peptide [R4w4] In Improving The Ability Of First-Line Antibiotics To Inhibit Mycobacterium Tuberculosis Inside In Vitro Human Granulomas, Joshua Hernandez, David Ashley, Ruoqiong Cao, Rachel Abrahem, Timothy Nguyen, Kimberly To, Aram Yegiazaryan, Ajayi Akinwale David, Rakesh Kumar Tiwari, Vishwanath Venketaraman

Pharmacy Faculty Articles and Research

Tuberculosis (TB) is currently one of the leading causes of global mortality. Medical non-compliance due to the length of the treatment and antibiotic side effects has led to the emergence of multidrug-resistant (MDR) strains of Mycobacterium tuberculosis (M. tb) that are difficult to treat. A current therapeutic strategy attempting to circumvent this issue aims to enhance drug delivery to reduce the duration of the antibiotic regimen or dosage of first-line antibiotics. One such agent that may help is cyclic peptide [R₄W₄], as it has been shown to have antibacterial properties (in combination with tetracycline) …

Comparative Molecular Transporter Properties Of Cyclic Peptides Containing Tryptophan And Arginine Residues Formed Through Disulfide Cyclization, Eman H. M. Mohammed, Dindyal Mandal, Saghar Mozaffari, Magdy Abdel-Hamied Zahran, Amany Mostafa Osman, Rakesh Kumar Tiwari, Keykavous Parang

Pharmacy Faculty Articles and Research

We have previously reported cyclic cell-penetrating peptides [WR]₅ and [WR]₄ as molecular transporters. To optimize further the utility of our developed peptides for targeted therapy in cancer cells using the redox condition, we designed a new generation of peptides and evaluated their cytotoxicity as well as uptake behavior against different cancer cell lines. Thus, cyclic [C(WR)_xC] and linear counterparts (C(WR)_xC), where x = 4–5, were synthesized using Fmoc/tBu solid-phase peptide synthesis, purified, and characterized. The compounds did not show any significant cytotoxicity (at 25 µM) against ovarian (SK-OV-3), leukemia (CCRF-CEM), gastric adenocarcinoma (CRL-1739), breast …

Recombinant Human Proteoglycan-4 Mediates Interleukin-6 Response In Both Human And Mouse Endothelial Cells Induced Into A Sepsis Phenotype, Holly A. Richendrfer, Mitchell M. Levy, Khaled A. Elsaid, Tannin A. Schmidt, Ling Zhang, Ralph Cabezas, Gregory D. Jay

Pharmacy Faculty Articles and Research

Objectives:

Sepsis is a leading cause of death in the United States. Putative targets to prevent systemic inflammatory response syndrome include antagonism of toll-like receptors 2 and 4 and CD44 receptors in vascular endothelial cells. Proteoglycan-4 is a mucinous glycoprotein that interacts with CD44 and toll-like receptor 4 resulting in a blockade of the NOD-like receptor pyrin domain-containing-3 pathway. We hypothesized that endothelial cells induced into a sepsis phenotype would have less interleukin-6 expression after recombinant human proteoglycan 4 treatment in vitro.

Design:

Enzyme-linked immunosorbent assay and reverse transcriptase-quantitative polymerase chain reaction to measure interleukin-6 protein and gene expression.

Setting: …

Proteoglycan-4 Regulates Fibroblast To Myofibroblast Transition And Expression Of Fibrotic Genes In The Synovium, Marwa Qadri, Gregory D. Jay, Ling X. Zhang, Holly Richendrfer, Tannin A. Schmidt, Khaled A. Elsaid

Pharmacy Faculty Articles and Research

Background: Synovial tissue fibrosis is common in advanced OA with features including the presence of stress fiber-positive myofibroblasts and deposition of cross-linked collagen type-I. Proteoglycan-4 (PRG4) is a mucinous glycoprotein secreted by synovial fibroblasts and is a major component of synovial fluid. PRG4 is a ligand of the CD44 receptor. Our objective was to examine the role of PRG4-CD44 interaction in regulating synovial tissue fibrosis in vitro and in vivo.

Methods: OA synoviocytes were treated with TGF-β ± PRG4 for 24h and α-SMA content was determined using immunofluorescence. Rhodamine-labeled rhPRG4 was incubated with OA synoviocytes ± anti-CD44 or …

Phenylpyrazalopyrimidines As Tyrosine Kinase Inhibitors: Synthesis, Antiproliferative Activity, And Molecular Simulations, Bhupender S. Chhikara, Sajda Ashraf, Saghar Mozaffari, Nicole St. Jeans, Dindyal Mandal, Rakesh Kumar Tiwari, Zaheer Ul-Haq, Keykavous Parang

Pharmacy Faculty Articles and Research

N1-(α,β-Alkene)-substituted phenylpyrazolopyrimidine derivatives with acetyl and functionalized phenyl groups at α- and β-positions, respectively, were synthesized by the reaction of 3-phenylpyrazolopyrimidine (PhPP) with bromoacetone, followed by a chalcone reaction with differently substituted aromatic aldehydes. The Src kinase enzyme assay revealed modest inhibitory activity (half maximal inhibitory concentration, IC₅₀ = 21.7–192.1 µM) by a number of PhPP derivatives. Antiproliferative activity of the compounds was evaluated on human leukemia (CCRF-CEM), human ovarian adenocarcinoma (SK-OV-3), breast carcinoma (MDA-MB-231), and colon adenocarcinoma (HT-29) cells in vitro. 4-Chlorophenyl carbo-enyl substituted 3-phenylpyrazolopyrimidine (10) inhibited the cell proliferation of HT-29 and SK-OV-3 by 90% …

Cd44 Receptor Mediates Urate Crystal Phagocytosis By Macrophages And Regulates Inflammation In A Murine Peritoneal Model Of Acute Gout, Emira Bousoik, Marwa Qadri, Khaled A. Elsaid

Pharmacy Faculty Articles and Research

Gout is a chronic arthritis caused by the deposition of poorly soluble monosodium urate monohydrate (MSU) crystals in peripheral joints. Resident macrophages initiate inflammation in response to MSU mediated by NF-κB nuclear translocation and NLRP3 inflammasome activation. We investigated the role of CD44, a transmembrane receptor, in mediating MSU phagocytosis by macrophages. We used an antibody that sheds the extracellular domain (ECD) of CD44 to study the role of the receptor and its associated protein phosphatase 2A (PP2A) in macrophage activation. We also studied the significance of CD44 in mediating MSU inflammation in-vivo. Cd44^−/− BMDMs showed reduced MSU …

Demarcation Of Sepsis-Induced Peripheral And Central Acidosis With Ph (Low) Insertion Cycle Peptide, Kelly E. Henry, Aisling M. Chaney, Veronica L. Nagle, Haley C. Cropper, Saghar Mozaffari, Chip Slaybaugh, Keykavous Parang, Oleg A. Andreev, Yana K. Reshetnyak, Michelle L. James, Jason S. Lewis

Pharmacy Faculty Articles and Research

Acidosis is a key driver for many diseases, including cancer, sepsis, and stroke. The spatiotemporal dynamics of dysregulated pH across disease remain elusive, and current diagnostic strategies do not provide localization of pH alterations. We sought to explore if PET imaging using hydrophobic cyclic peptides that partition into the cellular membrane at low extracellular pH (denoted as pH [low] insertion cycles, or pHLIC) can permit accurate in vivo visualization of acidosis. Methods: Acid-sensitive cyclic peptide c[E₄W₅C] pHLIC was conjugated to bifunctional maleimide-NO2A and radiolabeled with ⁶⁴Cu (half-life, 12.7 h). C57BL/6J mice were administered lipopolysaccharide (15 …

Glucocorticoids Rapidly Activate Camp Production Via GΑs To Initiate Non-Genomic Signaling That Contributes To One-Third Of Their Canonical Genomic Effects, Francisco J. Nuñez, Timothy B. Johnstone, Maia L. Corpuz, Austin G. Kazarian, Nicole N. Mohajer, Omar Tliba, Reynold A. Pannettieri Jr., Cynthia J. Koziol-White, Moom Roosan, Rennolds S. Ostrom

Pharmacy Faculty Articles and Research

Glucocorticoids are widely used for the suppression of inflammation, but evidence is growing that they can have rapid, non-genomic actions that have been unappreciated. Diverse cell signaling effects have been reported for glucocorticoids, leading us to hypothesize that glucocorticoids alone can swiftly increase the 3′,5′-cyclic adenosine monophosphate (cAMP) production. We found that prednisone, fluticasone, budesonide, and progesterone each increased cAMP levels within 3 minutes without phosphodiesterase inhibitors by measuring real-time cAMP dynamics using the cAMP difference detector in situ assay in a variety of immortalized cell lines and primary human airway smooth muscle (HASM) cells. A membrane- impermeable glucocorticoid showed …

Design And Biological Evaluation Of Colchicine-Cd44-Targeted Peptide Conjugate In An In Vitro Model Of Crystal Induced Inflammation, Khalid A. Zoghebi, Emira Bousoik, Keykavous Parang, Khaled A. Elsaid

Pharmacy Faculty Articles and Research

Gout is an inflammatory arthritis due to the joint deposition of monosodium urate (MSU) crystals. Phagocytosis of MSU crystals by tissue macrophages results in the generation of reactive oxygen species (ROS) and production of inflammatory cytokines and chemokines. Colchicine use in gout is limited by severe toxicity. CD44 is a transmembrane glycoprotein that is highly expressed in tissue macrophages and may be involved in gout pathogenesis. The P6 peptide is a 20-amino acid residue peptide that binds to CD44. We hypothesized that the conjugation of colchicine to the P6 peptide would reduce its off-target cytotoxicity while preserving its anti-inflammatory effect. …

Amphiphilic Cell-Penetrating Hybrid Cyclic-Linear Peptides As A Drug Delivery System, Saghar Mozaffari

Pharmaceutical Sciences (PhD) Dissertations

A number of cyclic peptides containing a positively charged ring composed of arginine residues attached to hydrophobic tail made of tryptophan residues through a lysine linker namely [R₅K]W₅, [R₆K]W₅, [R₅K]W₆, [R₇K]W₅, [R₅K]W₇, [R₆K]W₆, and [R₇K]W₇ were synthesized and evaluated as molecular transporters. The peptides were evaluated for their ability to deliver, fluorescence-labeled cell-impermeable negatively charged phosphopeptide (F′-GpYEEI), and fluorescent labeled anti-HIV drugs (F′-FTC and F′-d4T). The results indicated that the presence of positively …

A Systematic Comparison Of Lipopolymers For Sirna Delivery To Multiple Breast Cancer Cell Lines: In Vitro Studies, Hamidreza Montazeri Aliabadi, Remant Bahadur Kc, Emira Bousoik, Ashley Barbarino, Bindu Thapa, Melissa Coyle, Parvin Mahdipoor, Hasan Uludağ

Pharmacy Faculty Articles and Research

Small interfering RNA (siRNA) therapy is a promising approach for treatment of a wide range of cancers, including breast cancers that display variable phenotypic features. To explore the general utility of siRNA therapy to control aberrant expression of genes in breast cancer, we conducted a detailed analysis of siRNA delivery and silencing response in vitro in 6 separate breast cancer cell models (MDA-MB-231, MDA-MB-231-KRas-CRM, MCF-7, AU565, MDA-MB-435 and MDA-MB-468 cells). Using lipopolymers for siRNA complexation and delivery, we found a large variation in siRNA delivery efficiency depending on the specific lipopolymer used for siRNA complexation and delivery. Some lipopolymers were …

Chemical Epitope Targeting: Review Of A Novel Screening Technology, Qurrat Ul-Ain, Rene Kandler, Dylan Gillespie, Arundhati Nag

Scholarly Undergraduate Research Journal at Clark (SURJ)

Chemical Epitope Targeting is a novel technology developed for designing peptide ligands with high affinity and specificity against specific regions of a protein that may be inaccessible to small molecules or antibodies. In this review, we summarize the key steps and significant applications of this technology. Operating on the same principles as antibody-antigen interactions, this technique involves chemically synthesizing the region of interest on the protein, called the epitope, as a polypeptide with a biotin detection tag and a strategically placed alkyne or azide presenting amino acid. The constructed epitope is screened against a comprehensive linear or cyclic One Bead …

Edb-Fn Targeted Peptide–Drug Conjugates For Use Against Prostate Cancer, Shang Eun Park, Kiumars Shamloo, Timothy A. Kristedja, Shaban Darwish, Marco Bisoffi, Keykavous Parang, Rakesh Tiwari

Pharmacy Faculty Articles and Research

Prostate cancer (PCa) is the most common malignancy in men and is the leading cause of cancer-related male mortality. A disulfide cyclic peptide ligand [CTVRTSADC] 1 has been previously found to target extra domain B of fibronectin (EDB-FN) in the extracellular matrix that can dierentiate aggressive PCa from benign prostatic hyperplasia. We synthesized and optimized the stability of ligand 1 by amide cyclization to obtain [KTVRTSADE] 8 using Fmoc/tBu solid-phase chemistry. Optimized targeting ligand 8 was found to be stable in phosphate buered saline (PBS, pH 6.5, 7.0, and 7.5) and under redox conditions, with a half-life longer than 8 …

Molecular Recognition Of M1-Linked Ubiquitin Chains By Native And Phosphorylated Uban Domains, Lina Herhaus, Henry Van Den Bedem, Sean Teng, Innokentiy Maslennikov, Soichi Wakatsuki, Ivan Dikic, Simin Rahighi

Pharmacy Faculty Articles and Research

Although the Ub-binding domain in ABIN proteins and NEMO (UBAN) is highly conserved, UBAN-containing proteins exhibit different Ub-binding properties, resulting in their diverse biological roles. Post-translational modifications further control UBAN domain specificity for poly-Ub chains. However, precisely, how the UBAN domain structurally confers such functional diversity remains poorly understood. Here we report crystal structures of ABIN-1 alone and in complex with one or two M1-linked di-Ub chains. ABIN-1 UBAN forms a homo-dimer that provides two symmetrical Ub-binding sites on either side of the coiled-coil structure. Moreover, crystal structures of ABIN1 UBAN in complex with di-Ub chains reveal a concentration-dependency of …