Biomimetic Supramolecular Chemistry of Peptide Nucleic Acids

Abstract: DNA and RNA are naturally endowed with structural features for self-assembly through complementary base pairing, leading to a variety of structures ranging from hairpins, duplexes, triplexes to cruciform and tetraplexes etc. Several chemically modified analogues involving modification of sugar-phosphate backbone have been developed in the context of antisense and siRNA therapeutics. These analogues bind to complementary sequences via WC H-bonding from bases, but only from one side of the backbone. Peptide Nucleic Acids (PNA) are DNA analogues with nucleobases linked to pseudopeptide backbone instead of sugar-phosphate backbone and show sequence specific binding to complementary DNA and RNA with high affinity. We have now designed “Janus PNAs” that carry two different nucleobase sequences, one on each face of PNA. It is shown that such a Janus PNA can concurrently bind two different DNA/RNA sequences that enables them to target two different genes. We demonstrate the potential of “Janus” PNAs to form programmable assemblies such as double duplex, triplex of duplex and tetraduplex of tetraplex, with appropriate complementary DNA and RNA. Having multiple duplexes on a single backbone leads to synergistic effects on the thermal stability of each of the duplexes. Multistrand complexes from Janus PNAs can also be generated using Ag to bridge two C’s on one face and WC

H-bonding. Such polyplex materials offer new opportunities applications 

References

1. M. K. Gupta, B. R. Madhanagopal, D. Datta, K. N. Ganesh,. Org. Lett. 2020, 22, 5255−5260
   2. P. Bhingardeve, B. R. Madhanagopal, K. N. Ganesh, J. Org. Chem. 2020, 85, 13680−13693.
   3. M. K. Gupta, B. R. Madhanagopal, K. N. Ganesh J. Org. Chem. 2021, 86, 414−428.
   4. P. Bhingardeve, P. Jain, K. N. Ganesh, ACS Omega, 2021, 6, 19757−19770.
   5. I. A. Todkari, M. K. Gupta K. N. Ganesh, Chem. Commun. 2022, 58, 4083-4086.
   6. I. A. Todkari, P. Chaudhary, M. J. Kulkarni and Krishna N. Ganesh, Org. Biomol. Chem. 2024, 22, 6810.
   7. S. H. More, M. Schmutz, L. Jierry and K. N. Ganesh, Biomat Sci., 2024

Bio-sketch: Prof. Ganesh is a renowned scientist in the field of Nucleic Acid Chemistry and Biology with extensive research contributions on therapeutic and diagnostic applications of DNA analogues, structural biology of collagen peptides and the emerging area of DNA nanotechnology. He is well known for his contributions to design and develop Peptide Nucleic Acid (PNA) analogues for effective cell permeation. He has more than 175 publications in reputed international journals, 2 international patents and guided 49 students for their doctoral degrees. 

After his Bachelor and Master’s degree from Central College, Bangalore University (1972), his first PhD in Chemistry from Delhi University in 1976 and second one from the University of Cambridge, UK (1980). Prof. Ganesh Joined CCMB, Hyderabad in 1981, where he initiated Chemical synthesis of DNA and RNA during its formative years. He moved to National Chemical Laboratory, Pune in May 1987, to initiate a new program in Bioorganic chemistry of nucleic acids and peptides and served as Head, Organic Chemistry Division from 1993 to 2006. He is the Founder and first Director of two of the IISERs, Indian Institutes of Science Education Research (IISER) Pune (June 2006-October 2017) and Tirupati (November 2015- April 2023). Currently, he is SERB National Science Chair at JNCASR, Bengaluru.

Dr. Ganesh has received innumerable professional awards including Shanti Swarup Bhatnagar award of Chemical sciences (CSIR) and The World Academy of Science (TWAS) Prize for Chemical Sciences and has served as a member of the Editorial Advisory Boards of various journals including Chemistry, An Asian Journal (Wiley), J Organic Chemistry (ACS), Beilsten J Organic Chemistry, Oligonucleotides and Nucleic Acid Therapeutics. He is one of the founding Co-Editors of ACS Omega, the first open access journal of American Chemical Society, founded in 2016 and currently the Editor-in-Chief of ACS Omega. He served as the President of Division III of IUPAC during the years 2012-2013. He has also served as a member and Chair of several scientific committees of DST and DBT. He is currently the Chairman of DST – VAJRA committee and FIST Advisory Board. In addition he is also on Governing Council / Management Board of Symbiosis International University (Pune), SRM University (Chennai and Amaravati), Gujarat Biotechnology University (Gandhinagar), Member Management Coucil, JNCASR, Chairman Research Advisory Council of IISER Berhampur, and Past Chairman of the Governing Council of CeNS, Bengaluru.

Dr Ganesh is very active in teaching UG and PhD courses in spectroscopy, Chemistry of biology of peptides, nucleic acids and carbohydrates and chemical Biology. Due to his eminent contributions in research on nucleic acids, science education and Institution building, Government of India awarded the civilian honour “Padmashri” in 2023. Recently, in July 2024, Prof Ganesh was awarded CRSI Gold Medal.