Article
Microbiology
Lise Goltermann, Meiqin Zhang, Anna Elisabeth Ebbensgaard, Marija Fiodorovaite, Niloofar Yavari, Anders Lobner-Olesen, Peter E. Nielsen
Summary: The physical and chemical properties of the outer membrane of Gram-negative bacteria, including Escherichia coli, have a significant impact on the antibacterial activity and uptake of antibiotics. The composition of the outer lipopolysaccharide core plays a crucial role in determining the susceptibility to different peptide-nucleic acid conjugates.
FRONTIERS IN MICROBIOLOGY
(2022)
Article
Chemistry, Multidisciplinary
Mohadeseh Dastpeyman, John A. Karas, Azin Amin, Bradley J. Turner, Fazel Shabanpoor
Summary: Cell penetrating peptides (CPPs) are efficient vectors for intracellular delivery of biologically active agents like therapeutic antisense oligonucleotides (ASOs). Conjugating ASOs to CPPs through native chemical ligation (NCL) significantly improves their cellular permeability and therapeutic efficacy. This study demonstrates that chemo-selective NCL is a superior strategy for synthesizing bi-/trifunctional CPP-ASO conjugates with high efficiency.
FRONTIERS IN CHEMISTRY
(2021)
Review
Biochemistry & Molecular Biology
Kristina Klabenkova, Alesya Fokina, Dmitry Stetsenko
Summary: This article discusses the importance of peptide-oligonucleotide conjugates in enhancing the efficiency of therapeutic nucleic acids and the related chemical synthesis methods, which are mainly divided into two strategies: stepwise solid-phase synthesis and post-synthetic conjugation.
Article
Chemistry, Multidisciplinary
Chengxi Li, Alex J. Callahan, Kruttika S. Phadke, Bryan Bellaire, Charlotte E. Farquhar, Genwei Zhang, Carly K. Schissel, Alexander J. Mijalis, Nina Hartrampf, Andrei Loas, David E. Verhoeven, Bradley L. Pentelute
Summary: This study reports an efficient technology that utilizes a fully automated fast-flow instrument to manufacture cell-penetrating peptide-conjugated peptide nucleic acids (PPNAs), which improves cellular uptake. The synthesized PPNAs showed improved activity in splice-correction and antiviral assays. This technology has the potential to be used for further investigation of PPNA candidates as antiviral agents.
ACS CENTRAL SCIENCE
(2022)
Review
Biochemistry & Molecular Biology
Jessica Stoodley, Francisco Vallejo-Bedia, David Seone-Miraz, Manuel Debasa-Mouce, Matthew J. A. Wood, Miguel A. Varela
Summary: DM1 is a common muscular dystrophy that can potentially be treated with antisense therapy. Delivery of antisense molecules to target tissues remains a challenge, but conjugation to lipids, peptides, or antibodies has shown promise in improving therapeutic efficacy and tissue penetration. Clinical trials of antisense therapies are currently underway, raising hopes for an approved treatment for DM1 patients.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
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
Chemistry, Medicinal
Kentaro Tabara, Kazunori Watanabe, Hajime Shigeto, Shohei Yamamura, Takamasa Kishi, Mizuki Kitamatsu, Takashi Ohtsuki
Summary: This study introduces a new double-stranded PNA/DNA probe for miR-221 detection, showing higher target sensitivity and promising applications for miRNA diagnosis.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2021)
Article
Biochemistry & Molecular Biology
Alireza Japoni Nejad, Nader Shahrokhi, Peter E. Nielsen
Summary: In this study, a series of PNA-BPP conjugates targeting CRAB strains were designed and synthesized. These compounds demonstrated potent antimicrobial activity against CRAB, exhibiting complete growth inhibition at 1-2x MIC and sensitivity in 12 isolates. Additionally, the conjugates showed no bacterial membrane disruption activity and no cellular toxicity in HepG2 cells, indicating potential as precision designer antibiotics for specific treatment of CRAB infections.
Review
Chemistry, Multidisciplinary
Xingguo Liang, Mengqin Liu, Makoto Komiyama
Summary: Peptide nucleic acid (PNA) is a DNA analog widely used in chemistry, biochemistry, medicine, nanotechnology, and other fields. Recent developments have focused on designing PNA derivatives for specific recognition of DNA and RNA, leading to applications in gene expression regulation, gene editing, nanostructure construction, and more. The advantages and disadvantages of PNAs compared to other sequence-recognizing molecules are discussed in terms of physicochemical and biological features.
BULLETIN OF THE CHEMICAL SOCIETY OF JAPAN
(2021)
Article
Chemistry, Multidisciplinary
Christopher Liczner, Cameron C. Hanna, Richard J. Payne, Christopher J. Wilds
Summary: This study presents an efficient method for synthesizing peptide-oligonucleotide conjugates using a diselenide-selenoester ligation strategy, which leads to stable amide linkages between the two biomolecules. The novel conjugation strategy increases synthesis efficiency and expands the applications of chemical modification.
Article
Chemistry, Multidisciplinary
Carlo Diaferia, Concetta Avitabile, Marilisa Leone, Enrico Gallo, Michele Saviano, Antonella Accardo, Alessandra Romanelli
Summary: Peptides and nucleic acids can self-assemble to form supramolecular structures with different applications, and hydrogen bonds or aromatic interactions typically stabilize these structures; Watson-Crick pairing drives self-assembly in nucleic acids, while backbone hydrogen bonds and interactions between aromatic side chains trigger the formation of structures in peptides. Molecules containing aromatic peptides and nucleic acids can potentially utilize different forces for self-assembly.
CHEMISTRY-A EUROPEAN JOURNAL
(2021)
Review
Biophysics
Uladzislava Tsylents, Izabela Siekierska, Joanna Trylska
Summary: Peptide nucleic acid (PNA) is a nucleic acid mimic that shows great potential in antimicrobial applications due to its high specificity and resistance to degradation. However, the poor membrane permeability of PNA hinders its applications in cells. To overcome this limitation, PNA conjugates with various molecules, including cell-penetrating peptides, aminosugars, aminoglycoside antibiotics, and non-peptidic molecules, have been developed and tested as carriers for PNA in antibacterial and antiviral applications.
EUROPEAN BIOPHYSICS JOURNAL WITH BIOPHYSICS LETTERS
(2023)
Article
Biotechnology & Applied Microbiology
Vinay G. Joshi, Kantaraja Chindera, Manish Bais, Basavaraj Sajjanar, Ashok K. Tiwari, Satish Kumar
Summary: PNA is a chimeric molecule with advantages over natural antisense nucleic acid molecules, but faces challenges in cellular delivery due to its charge-neutral nature. The proposed novel RATH-2 peptide-based non-covalent PNA delivery mechanism showed promising results in cellular delivery and therapeutic application in antiviral intervention.
APPLIED MICROBIOLOGY AND BIOTECHNOLOGY
(2021)
Article
Chemistry, Organic
Jan-Erik Hornung, Timo Weinrich, Michael W. Goebel
Summary: Quinone methide precursors protected with alkyldithiomethyl groups have been synthesized and converted into PNA conjugates. These conjugates remain stable without reducing agents, but release electrophilic quinone methide in the presence of glutathione, typical of cytosolic concentrations. Self-alkylation or crosslinking of RNA occurs when hybridized with complementary strands, with the fastest reactions observed for the least hindered compound.
EUROPEAN JOURNAL OF ORGANIC CHEMISTRY
(2022)
Article
Biochemical Research Methods
Charlotte A. Henderson, Helen A. Vincent, Anastasia J. Callaghan
Summary: Regulatory RNA-based interactions play a critical role in coordinating gene expression and can be targeted for synthetic biology and antibacterial purposes. Modulating these interactions has the potential to reprogram gene expression and manipulate bacterial processes for specific applications. This novel pipeline offers a method for targeting RNA-based interactions with antisense oligonucleotides, providing a promising approach for gene expression manipulation.
ACS SYNTHETIC BIOLOGY
(2021)
Article
Biophysics
Tomasz Pienko, Jakub Czarnecki, Marcin Rownicki, Monika Wojciechowska, Aleksandra J. Wierzba, Dorota Gryko, Dariusz Bartosik, Joanna Trylska
Summary: By covalently linking vitamin B-12 with PNA, researchers were able to utilize the vitamin B-12 transport system to deliver PNA to E. coli cells. The conjugate follows the same route through the outer membrane as free vitamin B-12, with BtuB playing a crucial role in the transport process. Molecular dynamics simulations provided insights into the mechanism of conjugate permeation through BtuB, highlighting the potential for hijacking the vitamin B-12 system for efficient PNA delivery.
BIOPHYSICAL JOURNAL
(2021)
Article
Biochemistry & Molecular Biology
Adam Mieczkowski, Tomasz Fraczyk, Mateusz Psurski, Patrycja Winska, Pawel Siedlecki, Monika Dzielak, Damian Trzybinski, Marcin Wilczek, Maciej Baginski, Bartosz Bieszczad, Krzysztof Wozniak
Summary: The newly synthesized compounds showed enhanced activity and selectivity towards leukemic cell lines, while exhibiting weaker cytotoxic effects on other tumor cell lines and normal cells. These compounds may be promising for the development of selective anticancer therapies.
CHEMISTRY & BIODIVERSITY
(2021)
Article
Biochemistry & Molecular Biology
Adam Mieczkowski, Elzbieta Speina, Damian Trzybinski, Maria Winiewska-Szajewska, Patrycja Winska, Ewelina M. Borsuk, Malgorzata Podsiadla-Bialoskorska, Tomasz Przygodzki, Krzysztof Drabikowski, Lidia Stanczyk, Igor Zhukov, Cezary Watala, Krzysztof Wozniak
Summary: The study investigated the synthesis and cytotoxicity of novel analogues of the phosphodiesterase type 5 (PDE5) inhibitor-tadalafil, revealing that the parent compound exhibited stronger cytotoxic effects in most cases, except for specific cell lines. The newly obtained compounds showed no noticeable effect on PDE5 activity compared to the reference compound, suggesting potential for further research on selectivity and activity optimization for cytotoxic agents.
Article
Biochemistry & Molecular Biology
Piotr Chyzy, Marta Kulik, Suyong Re, Yuji Sugita, Joanna Trylska
Summary: Short, structured fragments of non-coding mRNA may act as molecular switches upon binding specific ligands, regulating the translation of proteins encoded downstream this mRNA sequence. The study reveals that nucleobase mutations in the riboswitch can significantly affect the affinity and efficiency of ligand regulation, with specific mutations altering the binding site position of neomycin and increasing its flexibility.
FRONTIERS IN MOLECULAR BIOSCIENCES
(2021)
Article
Biophysics
Natalia Ostrowska, Michael Feig, Joanna Trylska
Summary: Utilizing molecular dynamics simulations, this study investigates how crowded environments can influence the internal dynamics and diffusion of the hepatitis C virus proteases NS3/4A, suggesting that crowding may assist in the formation of an NS4A helical fragment and help the virus establish a replication machinery needed to produce new viruses. Results point to an active role of crowding in assisting structural changes in disordered protein fragments necessary for their biological function.
BIOPHYSICAL JOURNAL
(2021)
Article
Chemistry, Medicinal
Bartosz Bieszczad, Damian Garbicz, Marta Switalska, Marta K. Dudek, Dawid Warszycki, Joanna Wietrzyk, Elzbieta Grzesiuk, Adam Mieczkowski
Summary: In this study, a library of 19 analogues of Vorinostat was developed and tested for their HDAC inhibition and cytotoxic effects on cancer and normal cell lines. Three compounds based on dibenzo[b,f]azocin-6(5H)-one, 11,12-dihydrodibenzo[b,f]azocin-6(5H)-one, and benzo[b]naphtho[2,3-f][1,5]diazocine-6,14(5H,13H)-dione scaffolds showed better HDAC inhibition and lower IC50 values in leukemic and lymphoma cell lines compared to Vorinostat. These compounds exhibited higher activity and selectivity against specific cancer cell lines and a correlation between HDAC inhibition and cytotoxic effects was observed.
Article
Biochemistry & Molecular Biology
Alicja Dyzma, Beata Wielgus-Kutrowska, Agnieszka Girstun, Zoe Jelic Matosevic, Krzysztof Staron, Branimir Bertosa, Joanna Trylska, Agnieszka Bzowska
Summary: To investigate the reason for the trimeric structure of PNP, researchers constructed the monomeric form of the enzyme and found that the isolated monomer may have a non-functional active site. To confirm this, six amino acids at the subunit interface were mutated, resulting in a monomeric form (6Ala PNP) that showed no enzymatic activity. Simulation experiments revealed that the positions of the amino acids in the active site of 6Ala PNP significantly differed from the wild type, suggesting that a trimeric structure is necessary for stabilizing the active site geometry.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Chemistry, Physical
Daniel Baranowski, Adam Mieczkowski, Damian Trzybinski, Krzysztof Wozniak, Katarzyna Bednarska-Szczepaniak, Zofia Gdaniec, Zbigniew J. Lesnikowski
Summary: Detailed studies using NMR, crystallography, and ab initio methods were conducted on boron cluster-modified adenosine and 2'-deoxyadenosine derivatives, revealing consistent results. Introduction of bulky substituents at position C8 of adenosine resulted in increased population of syn conformation around the glycosidic bond, accompanied by a predominance of the South-type conformation and the presence of the + sc rotamer. Intramolecular hydrogen bond formation between 5 ' O -H and N3 was observed due to the coexistence of syn conformation, South-type conformation, and + sc rotamer. The crystal structures of adenosine-boron cluster derivatives were reported for the first time.
JOURNAL OF MOLECULAR STRUCTURE
(2023)
Article
Biochemistry & Molecular Biology
Elzbieta Speina, Marcin Wilczek, Adam Mieczkowski
Summary: In this study, a synthesis method for two benzodiazepine dimers was developed, and the synthesized compounds showed promising cytotoxic activity against lung cancer and carcinoma cell lines while exhibiting selectivity against normal cells. These compounds can be considered as a new group of anticancer agents and convenient structures for further optimization in the search for more active and selective molecules.
Article
Biochemical Research Methods
Natalia Ostrowska, Michael Feig, Joanna Trylska
Summary: Enzyme-catalyzed reactions occur in crowded conditions in the cell, and viral enzymes in host cells also encounter such crowded conditions. The NS3/4A protease encoded by the hepatitis C virus is an important enzyme for viral replication. Synthetic crowders (polyethylene glycol and polysucrose) differently affect the enzyme's kinetic parameters and structural dynamics. Crowders slow down enzyme diffusion, induce helical structures in the protease cofactor, and interact with substrates. Crowders enhance substrate binding and affect enzyme-substrate interactions.
PLOS COMPUTATIONAL BIOLOGY
(2023)
Article
Chemistry, Multidisciplinary
Julia Macyszyn, Michal Burmistrz, Adam Mieczkowski, Monika Wojciechowska, Joanna Trylska
Summary: The misuse and overuse of antibiotics has led to bacterial resistance, limiting the use of existing aminoglycoside antibiotics. To combat multidrug-resistant bacteria, researchers have developed a combination of neomycin and amikacin with an antimicrobial peptide called anoplin. These hybrid compounds have shown enhanced antibacterial activity against resistant strains and low hemolytic activity.
Review
Biochemistry & Molecular Biology
Katherine Burchiellaro, Adam Mieczkowski
Summary: Cyclonucleosides are nucleoside derivatives with an additional covalent bond connecting the heterocyclic base and sugar ring. They have various applications in medicinal chemistry and biochemistry, and can act as biocides, enzyme inhibitors, and molecular probes. This review summarizes recent progress in the synthesis of purine and pyrimidine cyclonucleosides using different chemical approaches, and discusses their potential applications in medicinal chemistry and as valuable intermediates in the synthesis of nucleoside analogues and heterocyclic compounds.
MOLECULAR DIVERSITY
(2023)
Article
Multidisciplinary Sciences
Julia Macyszyn, Piotr Chyzy, Michal Burmistrz, Malgorzata Lobka, Joanna Miszkiewicz, Monika Wojciechowska, Joanna Trylska
Summary: This study modified a cell-penetrating peptide (KFF)(3)K by introducing a hydrocarbon staple into the sequence, transforming it into an antibacterial peptide. The stapled analogues showed antibacterial activity against various strains, in contrast to the unmodified peptide. Additionally, the stapled peptides exhibited improved protease resistance and a more defined secondary structure compared to the unstapled peptide.
SCIENTIFIC REPORTS
(2023)
Meeting Abstract
Biochemistry & Molecular Biology
Julia Macyszyn, Monika Wojciechowska, Joanna Miszkiewicz, Joanna Trylska
JOURNAL OF PEPTIDE SCIENCE
(2022)
