Article
Chemistry, Multidisciplinary
Fa-Jie Chen, Nicole Pinnette, Fan Yang, Jianmin Gao
Summary: In this study, we report a cysteine-directed proximity-driven strategy for constructing bicyclic peptides from simple natural peptide precursors. This linear to bicycle transformation involves rapid cysteine labeling and subsequent amine-selective cyclization. The bicyclization process occurs rapidly under physiological conditions, resulting in bicyclic peptides with Cys-Lys-Cys, Lys-Cys-Lys, or N-terminus-Cys-Cys stapling patterns. We demonstrate the utility and power of this strategy by constructing bicyclic peptides fused to proteins and the M13 phage, enabling the phage display of novel bicyclic peptide libraries.
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
(2023)
Article
Pharmacology & Pharmacy
Mohadeseh Dastpeyman, Ramin Sharifi, Azin Amin, John A. Karas, Brittany Cuic, Yijun Pan, Joseph A. Nicolazzo, Bradley J. Turner, Fazel Shabanpoor
Summary: This study demonstrates that integrating endosomal escape domains with CPPs can improve the intracellular delivery efficiency of ASOs, and enhance the efficiency of BBB-permeability and CNS activity of systemically administered ASOs.
INTERNATIONAL JOURNAL OF PHARMACEUTICS
(2021)
Article
Chemistry, Multidisciplinary
Chuan Wan, Zhanfeng Hou, Dongyan Yang, Ziyuan Zhou, Hongkun Xu, Yuena Wang, Chuan Dai, Mingchan Liang, Jun Meng, Jiean Chen, Feng Yin, Rui Wang, Zigang Li
Summary: Visible-light-mediated methods for cysteine-selective bioconjugation suffer from bio-incompatible conditions and slow kinetics. Here, we report a transition metal-free thiol-sulfoxonium ylide photo-click reaction that enables bioconjugation under bio-compatible conditions. It demonstrates high cysteine-selectivity and rapid reaction kinetics using riboflavin derivatives as photocatalysts. This method provides efficient tools for exploring the druggable content of the human proteome.
Article
Chemistry, Multidisciplinary
Nitin A. Patil, Varsha J. Thombare, Rong Li, Xiaoji He, Jing Lu, Heidi H. Yu, Hasini Wickremasinghe, Kavya Pamulapati, Mohammad A. K. Azad, Tony Velkov, Kade D. Roberts, Jian Li
Summary: Peptide-Peptide Nucleic Acid (PNA) conjugates have shown potential in developing novel antisense antimicrobials. The efficiency of Cys-CINA conjugation was investigated for synthesizing peptide-PNA conjugates, which demonstrated improved antimicrobial activity against multidrug-resistant Gram-negative bacteria.
FRONTIERS IN CHEMISTRY
(2022)
Article
Biochemical Research Methods
Gemma E. Mudd, Steven J. Stanway, David R. Witty, Alex Thomas, Silvia Baldo, Andrew D. Bond, Paul Beswick, Adrian Highton
Summary: Bicycles are constrained bicyclic peptides formed through the reaction of cysteine residues with a small molecule scaffold. The use of gold-mediated arylation offers a general method for the construction of highly constrained Bicycles, with high selectivity and efficiency.
BIOCONJUGATE CHEMISTRY
(2022)
Article
Chemistry, Multidisciplinary
Carly K. Schissel, Somesh Mohapatra, Justin M. Wolfe, Colin M. Fadzen, Kamela Bellovoda, Chia-Ling Wu, Jenna A. Wood, Annika B. Malmberg, Andrei Loas, Rafael Gomez-Bombarelli, Bradley L. Pentelute
Summary: The study demonstrates that deep learning can decipher design principles to generate highly active biomolecules, such as Mach proteins, which are capable of delivering antisense cargo efficiently without toxicity in mice. This approach combines high-throughput experimentation with a deep-learning method inspired by directed evolution, representing molecular structures as topological fingerprints.
Article
Biochemistry & Molecular Biology
Annika Klimpel, Katharina Stillger, Janica L. Wiederstein, Marcus Krueger, Ines Neundorf
Summary: Cysteine prenylation is a post-translational modification that controls important biological functions of proteins. This modification mainly occurs at the C-terminal CaaX box of eukaryotic proteins. New tools, such as cell-permeable peptides with a CaaX motif, have been developed to study and regulate this modification.
Article
Biochemical Research Methods
Martina Traykovska, Katya B. Popova, Robert Penchovsky
Summary: This study developed novel chimeric antisense oligonucleotides targeting glmS riboswitch and nagA mRNA to inhibit the growth of Staphylococcus aureus by blocking bacterial metabolic pathways. The specific targeting of glmS riboswitch was found to be sufficient to inhibit the bacterial growth, making it a promising target for antibacterial drug development using antisense oligonucleotides.
ACS SYNTHETIC BIOLOGY
(2021)
Review
Cell Biology
Umme Sabrina Haque, Toshifumi Yokota
Summary: Antisense oligonucleotide-based therapeutics have great potential for treating human disorders, while the efficient delivery to target cells remains a challenge. Cell-penetrating peptides (CPPs), especially DG9 peptide, show promise in enhancing the cellular uptake and intracellular delivery of oligonucleotide-based drugs. Several studies have demonstrated the potential of DG9-conjugated PMOs in treating DMD and SMA in animal models.
Article
Chemistry, Multidisciplinary
Aline D. Araujo, Huy N. Hoang, Junxian Lim, Jeffrey Y. W. Mak, David P. Fairlie
Summary: Summary: Aromatic groups play a crucial role in protein-membrane association and cell uptake. The electrostatic and hydrophobic properties of aromatic ring substituents influence the affinity towards phospholipid membranes. The combination of fluorine and sulfur substituents induces microdipoles, enhancing the cell uptake of peptides.
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
(2022)
Article
Nanoscience & Nanotechnology
Huiying Xu, Chong Liao, Shifu Liang, Bang-Ce Ye
Summary: Exosomes are natural delivery vehicles with features like low immunogenicity, excellent biocompatibility, and migration capability. This study developed a novel peptide-equipped exosomes platform that can improve cellular uptake efficiency and deliver nucleic acids effectively, showing potential for personalized cancer medicine.
ACS APPLIED MATERIALS & INTERFACES
(2021)
Article
Biophysics
Maria Chiarpotti, Gabriel S. Longo, Mario G. Del Popolo
Summary: In this study, the adsorption of nanoparticles coated with CPP on membranes containing acidic lipids was characterized using a molecular theory. The results show that electrostatic interactions, modulated by entropic effects, provide the driving force and regulate the adsorption kinetics of CPP-coated particles on acidic membranes. Adsorption free energy profiles allow to quantify the adsorption energy, and reveal that nanoparticles attachment and detachment from the membrane surface are restrained by free energy barriers.
COLLOIDS AND SURFACES B-BIOINTERFACES
(2021)
Review
Infectious Diseases
Nikolet Pavlova, Martina Traykovska, Robert Penchovsky
Summary: This article describes the rational design and applications of chimeric antisense oligonucleotides as antibacterial agents targeting riboswitches. By targeting specific riboswitches, the aim is to combat antibiotic-resistant bacteria and enhance the efficacy of antibacterial treatments. Experimental results demonstrate that these riboswitches are suitable targets for antibacterial drug development using antisense oligonucleotide technology.
Article
Biochemistry & Molecular Biology
Ly Porosk, Heleri Heike Hark, Renata Naporano Bicev, Ilja Gaidutsik, Jekaterina Nebogatova, Eger-Jasper Armolik, Piret Arukuusk, Emerson Rodrigo da Silva, Ulo Langel
Summary: Alzheimer's disease (AD) is a common neurodegenerative disease that causes dementia, and its pathophysiological dynamics are driven by genetics with high heterogeneity in biological alterations and causes. The disease is characterized by the progression of aggregated amyloid-beta (A beta) or Tau neurofibrillary tangles. Current treatments for AD are not efficient, but recent breakthroughs have led to the discovery of potential therapeutic targets such as reducing brain inflammation and limiting A beta aggregation. This study demonstrates the successful use of A beta interacting protein sequences, particularly derived from Transthyretin, to reduce or target amyloid aggregation, and also predicts anti-inflammatory properties.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Review
Biochemistry & Molecular Biology
Hangfei Chen, Dheerendranath Battalapalli, Mohamed S. Draz, Pengfei Zhang, Zhi Ruan
Summary: This review discusses the characteristics, designing strategies, and recent progress in the development and application of antimicrobial CPPs as potent antibacterial agents against multidrug-resistant bacteria, providing a new approach to combating multidrug-resistant bacteria.
CURRENT MEDICINAL CHEMISTRY
(2021)
Article
Chemistry, Multidisciplinary
Muhammad Jbara, Sebastian Pomplun, Carly K. Schissel, Susana Wilson Hawken, Ann Boija, Isaac Klein, Jacob Rodriguez, Stephen L. Buchwald, Bradley L. Pentelute
Summary: Novel synthetic TF mimetics have been developed to inhibit oncogenic Myc-driven transcription by antagonistic DNA-binding, leading to reduced cancer cell proliferation. The use of flow chemistry and palladium(II) OACs offers a practical strategy to generate bioactive compounds for inhibiting tumor cell proliferation.
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
(2021)
Article
Chemistry, Multidisciplinary
Genwei Zhang, Joseph S. Brown, Anthony J. Quartararo, Chengxi Li, Xuyu Tan, Stephanie Hanna, Sarah Antilla, Amanda E. Cowfer, Andrei Loas, Bradley L. Pentelute
Summary: The study reports the discovery of high affinity peptidomimetic binders to angiotensin converting enzyme 2 (ACE2) using affinity selection-mass spectrometry. The noncanonical binder ABP N1 showed enhanced serum stability compared to the canonical binder ABP C7. ABP N1 was able to selectively detect picomolar to low nanomolar concentrations of ACE2 in human serum using an enzyme-linked immunosorbent assay.
COMMUNICATIONS CHEMISTRY
(2022)
Correction
Chemistry, Multidisciplinary
Martin Gazvoda, Heemal H. Dhanjee, Jacob Rodriguez, Joseph S. Brown, Charlotte E. Farquhar, Nicholas L. Truex, Andrei Loas, Stephen L. Buchwald, Bradley L. Pentelute
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
(2022)
Article
Chemistry, Multidisciplinary
Martin Gazvoda, Heemal H. Dhanjee, Jacob Rodriguez, Joseph S. Brown, Charlotte E. Farquhar, Nicholas L. Truex, Andrei Loas, Stephen L. Buchwald, Bradley L. Pentelute
Summary: This article describes a method for embedding carborane moieties into small molecules, peptides, and proteins. The strategy involves palladium-mediated C-X bond formation and enables selective conjugation of carborane-containing groups with other molecules in aqueous buffer. The method has been successfully applied to nanobodies, fully synthetic affibodies, and antibody therapeutics such as Herceptin and Cetuximab.
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
(2022)
Article
Multidisciplinary Sciences
Kyan A. D'Angelo, Carly K. Schissel, Bradley L. Pentelute, Mohammad Movassaghi
Summary: The study presents a concise total synthesis method for himastatin, a natural product with an unusual homodimeric structure. The final-stage dimerization strategy used in the synthesis was inspired by a detailed understanding of the compound's biogenesis. By combining this approach with a modular synthesis, a series of designed derivatives of himastatin, including synthetic probes to investigate its antibiotic activity, were efficiently accessed.
Article
Chemistry, Multidisciplinary
Chengxi Li, Genwei Zhang, Somesh Mohapatra, Alex J. Callahan, Andrei Loas, Rafael Gomez-Bombarelli, Bradley L. Pentelute
Summary: This study leverages machine learning algorithms and automated synthesis technology to predict PNA synthesis efficiency and validate the predicted sequences through design.
Article
Chemistry, Multidisciplinary
Xiyun Ye, Yen-Chun Lee, Zachary P. Gates, Yingjie Ling, Jennifer C. Mortensen, Fan-Shen Yang, Yu-Shan Lin, Bradley L. Pentelute
Summary: Alanine substitution in peptides is crucial for studying peptide-based inhibitors of protein-protein interactions, but limited information is obtained from single alanine substitution. Here, the authors develop a label-free combinatorial alanine affinity selection platform to establish multi-alanine mutational tolerance and provide structure-activity relationships.
COMMUNICATIONS CHEMISTRY
(2022)
Article
Biochemistry & Molecular Biology
Carly K. Schissel, Charlotte E. Farquhar, Andrei Loas, Annika B. Malmberg, Bradley L. Pentelute
Summary: Peptide-mediated delivery of macromolecules in cells has potential therapeutic benefits, but finding efficient sequences has been a challenge. In this study, a method called in-cell PS-MS was developed to discover peptides capable of delivering macromolecule cargo to the cytosol. One representative peptide, Cyto1a, was found to be more active and less toxic than known CPPs with similar activity. This method provides a means to discover synthetic peptides for subcellular delivery of therapeutically relevant cargo.
ACS CHEMICAL BIOLOGY
(2023)
Article
Chemistry, Multidisciplinary
Xiyun Ye, Peiyuan Zhang, John C. K. Wang, Corey L. Smith, Silvino Sousa, Andrei Loas, Dan L. Eaton, Magdalena Preciado Lopez, Bradley L. Pentelute
Summary: a-Klotho, an aging-related protein, regulates serum phosphate and vitamin D levels by acting as a co-receptor with the fibroblast growth factor 23 receptor complex. This study developed branched peptides that can recognize a-Klotho with improved affinity and selectively label Klotho for live imaging in kidney cells. The automated flow technology used in this study shows promise for future detection of a-Klotho in physiological settings.
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
(2023)
Article
Chemistry, Multidisciplinary
Kohei Sato, Charlotte E. Farquhar, Jacob Rodriguez, Bradley L. Pentelute
Summary: An expansion of the hexanucleotide repeat sequence in the chromosome 9 open frame 72 (c9orf72) is the most common genetic mutation in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). This mutation leads to the production of toxic dipeptide repeat proteins (DPRs) that induce neurodegeneration. In this study, the researchers synthesized various DPRs using automated fast-flow peptide synthesis (AFPS) and revealed their physical properties, including secondary structures. They also demonstrated the cytotoxic effects of specific DPRs on human neuroblastoma cells. This research highlights the potential of AFPS in synthesizing peptides and proteins for studying disease mechanisms and constructing disease models.
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
(2023)
Article
Multidisciplinary Sciences
Simon L. Rossler, Nathalie M. Grob, Stephen L. Buchwald, Bradley L. Pentelute
Summary: This study establishes abiotic peptides as carriers of information for the encoding of small-molecule synthesis. These peptides are used to encode diverse small-molecule synthesis and successfully discover protein ligands. This work demonstrates the potential for abiotic peptides in accelerating the discovery of therapeutic targets.
Article
Chemistry, Multidisciplinary
Nicholas L. Truex, Aureïlie Rondon, Simon L. Ro''ssler, Cameron C. Hanna, Yehlin Cho, Bin-You Wang, Coralie M. Backlund, Emi A. Lutz, Darrell J. Irvine, Bradley L. Pentelute
Summary: This study engineered an antigen peptide delivery system to improve the efficacy of vaccines by targeting dendritic cells and facilitating cytosolic delivery. The results demonstrate that this system enhances immune responses and significantly inhibits tumor growth and improves survival rates in mice.
ACS CENTRAL SCIENCE
(2023)
Article
Chemistry, Multidisciplinary
Anthony J. Rojas, Justin M. Wolfe, Heemal H. Dhanjee, Ivan Buslov, Nicholas L. Truex, Richard Y. Liu, Walter Massefski, Bradley L. Pentelute, Stephen L. Buchwald
Summary: The synthesis of palladium oxidative addition complexes derived from unprotected peptides is described. These complexes can react with thiols in aqueous buffer, providing an efficient method for bioconjugation. Using this strategy, peptides can be functionalized with small molecules to prepare modified aryl thioether side-chains at low micromolar concentrations. Additionally, peptide-peptide and peptide-protein ligations are demonstrated under dilute aqueous conditions.
Article
Chemistry, Multidisciplinary
Eva M. Lopez-Vidal, Carly K. Schissel, Somesh Mohapatra, Kamela Bellovoda, Chia-Ling Wu, Jenna A. Wood, Annika B. Malmberg, Andrei Loas, Rafael Gomez-Bombarelli, Bradley L. Pentelute
Summary: Cell-penetrating peptides (CPPs) are able to deliver therapeutic macromolecules into cells, but designing effective CPPs can be challenging. By using machine learning and extrapolation from data sets, short, active CPP sequences can be discovered.
Article
Chemistry, Multidisciplinary
Genwei Zhang, Chengxi Li, Anthony J. Quartararo, Andrei Loas, Bradley L. Pentelute
Summary: The study introduces an automated BLI-assisted affinity selection platform that enables rapid discovery of new binders and affinity maturation of known peptide binders with high selectivity. This technology also offers real-time monitoring of peptide binding during the selection process, a feature not achievable by current methods.