skip to main content
US FlagAn official website of the United States government
dot gov icon
Official websites use .gov
A .gov website belongs to an official government organization in the United States.
https lock icon
Secure .gov websites use HTTPS
A lock ( lock ) or https:// means you've safely connected to the .gov website. Share sensitive information only on official, secure websites.

Explore Research Products in the PAR
It may take a few hours for recently added research products to appear in PAR search results.


Title: Chemical approaches to discover the full potential of Peptide Nucleic Acids in biomedical applications
Peptide Nucleic Acid (PNA) is arguably one of the most successful DNA mimics, despite a most dramatic departure from the native structure of DNA. The present review summarizes 30 years of research on PNA’s chemistry, optimization of structure and function, applications as probes and diagnostics, and attempts to develop new PNA therapeutics. The discussion starts with a brief review of PNA’s binding modes and structural features, followed by the most impactful chemical modifications, PNA enabled assays and diagnostics, and discussion of the current state of development of PNA therapeutics. While many modifications have improved on PNA’s binding affinity and specificity, solubility and other biophysical properties, the original PNA is still most frequently used in diagnostic and other in vitro applications. Development of therapeutics and other in vivo applications of PNA has notably lagged behind and is still limited by insufficient bioavailability and difficulties with tissue specific delivery. Relatively high doses are required to overcome poor cellular uptake and endosomal entrapment, which increases the risk of toxicity. These limitations remain unsolved problems waiting for innovative chemistry and biology to unlock the full potential of PNA in biomedical applications.  more » « less
Award ID(s):
1708761
PAR ID:
10302073
Author(s) / Creator(s):
; ; ; ;
Date Published:
Journal Name:
Beilstein journal of organic chemistry
Volume:
17
ISSN:
1860-5397
Page Range / eLocation ID:
1641–1688
Format(s):
Medium: X
Sponsoring Org:
National Science Foundation
More Like this
  1. ; ; ; ; ; ; ; ; (, Synlett)
    Abstract Triplex-forming peptide nucleic acids (PNAs) require chemical modifications for efficient sequence-specific recognition of DNA and RNA at physiological pH. Our research groups have developed 2-aminopyridine (M) as an effective mimic of protonated cytosine in C+•G-C triplets. M-modified PNAs have a high binding affinity and sequence specificity as well as promising biological properties for improving PNA applications. This communication reports the optimization of synthetic procedures that give PNA M monomer in seven steps, with minimal need for column chromatography and in good yields and high purity. The optimized route uses inexpensive reagents and easily performed reactions, which will be useful for the broad community of nucleic acid chemists. Thought has also been given to the potential for future development of industrial syntheses of M monomers. 
    more » « less
  2. ; ; ; (, Annual Review of Physical Chemistry)
    This review provides focused coverage of the photophysical properties of noncanonical and synthetic nucleobases reported over the past decade. It emphasizes key research findings and physical insights gathered for prebiotic and fluorescent nucleobase analogs, sulfur- and selenium-substituted nucleobases, aza-substituted nucleobases, epigenetic nucleobases and their oxidation products, and nucleobases utilized for expanding DNA/RNA to reveal central structure–photophysical property relationships. Further research and development in this emerging field, coupled with machine learning methods, will enable the effective harnessing of nucleobases’ modifications for applications in biotechnology, biomedicine, therapeutics, and even the creation of live semisynthetic organisms. 
    more » « less
  3. ; (, Advanced Materials)
    Abstract Biomolecule isolation is a crucial process in diverse biomedical and biochemical applications, including diagnostics, therapeutics, research, and manufacturing. Recently, MXenes, a novel class of two‐dimensional nanomaterials, have emerged as promising adsorbents for this purpose due to their unique physicochemical properties. These biocompatible and antibacterial nanomaterials feature a high aspect ratio, excellent conductivity, and versatile surface chemistry. This timely review explores the potential of MXenes for isolating a wide range of biomolecules, such as proteins, nucleic acids, and small molecules, while highlighting key future research trends and innovative applications poised to transform the field. This review provides an in‐depth discussion of various synthesis methods and functionalization techniques that enhance the specificity and efficiency of MXenes in biomolecule isolation. In addition, the mechanisms by which MXenes interact with biomolecules are elucidated, offering insights into their selective adsorption and customized separation capabilities. This review also addresses recent advancements, identifies existing challenges, and examines emerging trends that may drive the next wave of innovation in this rapidly evolving area. 
    more » « less
  4. ; (, Organic & Biomolecular Chemistry)
    The tumor suppressor and master gene regulator protein p53 has been the subject of intense investigation for several decades due to its mutation in about half of all human cancers. However, mechanistic studies of p53 in cells are complicated by its many dynamic binding partners and heterogeneous post-translational modifications. The design of therapeutics that rescue p53 functions in cells requires a mechanistic understanding of its protein–protein interactions in specific protein complexes and identifying changes in p53 activity by diverse post-translational modifications. This review highlights the important roles that peptide and protein chemistry have played in biophysical and biochemical studies aimed at elucidating p53 regulation by several key binding partners. The design of various peptide inhibitors that rescue p53 function in cells and new opportunities in targeting p53-protein interactions are discussed. In addition, the review highlights the importance of a protein semisynthesis approach to comprehend the role of site-specific PTMs in p53 regulation. 
    more » « less
  5. ; ; (, ChemBioChem)
    Peptide nucleic acid (PNA) forms a triple helix with double‐stranded RNA (dsRNA) stabilized by a hydrogen‐bonding zipper formed by PNA’s backbone amides (N‐H) interacting with RNA phosphate oxygens. This hydrogen‐bonding pattern is enabled by the matching ~5.7 Å spacing (typical for A‐form dsRNA) between PNA’s backbone amides and RNA phosphate oxygens. We hypothesized that extending the PNA’s backbone by one ‐CH2‐ group may bring the distance between PNA amide N‐H closer to 7 Å, favourable for hydrogen‐bonding to the B‐form dsDNA phosphate oxygens. Extension of PNA backbone was expected to selectively stabilize PNA‐DNA triplexes compared to PNA‐RNA. To test this hypothesis, we synthesized triplex‐forming PNAs that had the pseudopeptide backbones extended by an additional ‐CH2‐ group in three different positions. Isothermal titration calorimetry measurements of the binding affinity of these extended PNA analogues for the matched dsDNA and dsRNA showed that, contrary to our structural reasoning, extending the PNA backbone at any position had a strong negative effect on triplex stability. Our results suggest that PNA may have an inherent preference for A‐form‐like conformations when binding double‐stranded nucleic acids. It appears that the original six atoms long PNA backbone is an almost perfect fit for binding to A‐form nucleic acids. 
    more » « less
  • Citation Formats
  • MLA
  • APA
  • Chicago
  • BibTeX
  • Text Encoded Conversion
  • XML
  • Save / Share this Record
  • Send to Email