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Moscow

Physics
physics@uidaho.edu
phone: (208) 885-6380
Engineering Physics Rm 311
875 Perimeter Drive Stop 0903
Moscow, ID 83844-0903

Bioorganic Chemistry

Hrdlicka Laboratory

Introduction
Several diseases are triggered by pathogenic proteins, which are encoded by DNA. Traditional drugs target these proteins directly but there are other ways...Significant efforts have been directed towards preventing the formation of pathogenic proteins by using short oligonucleotides (ONs) as potential antigene (targeting double-stranded DNA) or antisense (targeting single-stranded mRNA) therapeutics. Hereby, transcription or translation is blocked and the protein is not expressed in the cell. The advantage of these therapeutic strategies is that the disease is fought at an early stage and that doses can be reduced.

ONs must be chemically modified to bind harder to the target dsDNA (antigene) or mRNA (antisense) and to confer protection from enzymatic degradation. Incorporation of nucleosides such as LNA (locked nucleic acid) or ?-L-LNA that have conformationally restricted carbohydrate rings into ONs has been an especially popular approach to realize this.

More recently, nucleic acids have been used to generate nanometer-sized "e;machines" or electronic circuits. The applicability of nucleic acids to nanotechnology arises due to:

 a) their self-assembly as governed by the Watson-Crick base-pairing rules giving predictable 3-D structures,
 b) the well-defined and naturally nanometer sized dimensions of nucleic acid complexes and
 c) the fairly straightforward synthesis of nucleic acids.

Research
Depending on your interests, projects can be designed which focus on:
  • design, synthesis and biophysical evaluation of new functionalized nucleotide building blocks, including members from the LNA family.
  • characterization of nucleic acid duplexes by molecular modeling
  • characterization of new building blocks within antisense/antigene strategies and other gene regulatory strategies
  • development of conceptually new methods for targeting dsDNA, with the aim to generate new types of therapeutics
  • development of new strategies for nucleic acid based diagnostics using fluorescently labeled nucleotides
  • applying functionalized nucleotides to generate nanometer-sized smart devices which, e.g., are able to perform precise movements or to act as efficient catalysts
The experimental disciplines that you would normally encounter as a member of my research team are therefore: 
  • synthetic organic chemistry (carbohydrate/nucleoside/heterocyclic/organometallic reactions,…) 
  • purification techniques (HPLC, column chromatography, crystallization,…) 
  • structural elucidation (NMR, MS, X-ray,…) 
  • solid-phase chemistry 
  • fluorescence spectroscopy 
  • molecular modeling (force field, ab initio)
If you are considering to work within this interdisciplinary field in a remodeled and well-equipped laboratory, I would recommend you to contact me by e-mail for further inquiry regarding projects or check out some of our recent publications; I recommend 2, 6-8, and 13.

Publications:

14.
Andreas S. Madsen, Patrick J. Hrdlicka, T. Santhosh Kumar and Jesper Wengel.*
"Synthesis, Nucleic Acid Hybridization Properties and Molecular Modeling Studies of Conformationally Restricted 3'-O,4'-C-Methylene-Linked ?-L-Ribonucleotides"
Carbohydr. Res. 2006, 341, 1398-1407.

13.
T. Santhosh Kumar, Andreas S. Madsen, Jesper Wengel and Patrick J. Hrdlicka.*
"Synthesis and Hybridization Studies of 2’-Amino-?-L-LNA and a Tetracyclic 'Locked LNA' "
J. Org. Chem. 2006, 71, 4188-4201.

12.
Patrick J. Hrdlicka, T. Santhosh Kumar and Jesper Wengel.*
"Synthesis and Thermal Denaturation Studies of Conformationally Restricted 3'-C-Ethynyl-3'-O,4'-C-Methyleneribonucleotides"
Eur. J. Org. Chem. 2005, 5184-5188.

11.
Patrick J. Hrdlicka, T. Santhosh Kumar and Jesper Wengel.*
"Synthesis of a 2’-Amino-?-L-LNA-T Phosphoramidite"
Nucleosides Nucleotides Nucleic Acids 2005, 24, 1101-1104.

10.
Patrick J. Hrdlicka,* Jan S. Jepsen and Jesper Wengel.
"Synthesis and Biological Evaluation of Conformationally Restricted and Nucleobase-modified Analogs of the Anticancer Compound 3'-C-Ethynylcytidine (ECyd)"
Nucleosides Nucleotides Nucleic Acids 2005, 24, 397-400.

9.
Patrick J. Hrdlicka, B. Ravindra Babu, Mads D. Sørensen, Niels Harrit and Jesper Wengel.*
"Ångström-scale Chemical Engineering: Multilabeled 2'-Amino-LNA Probes for Nucleic Acid Detection in Homogenous Fluorescence Assays"
In: Collection Symposium Series (M. Hocek, Ed.), 7 (Chemistry of Nucleic Acid Components), 27-28, Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, Prague 2005. (not peer-reviewed)

8.
Patrick J. Hrdlicka, B. Ravindra Babu, Mads D. Sørensen, Niels Harrit and Jesper Wengel.*
"Multilabeled Pyrene-Functionalized 2'-Amino-LNA Probes for Nucleic Acid Detection in Homogenous Fluorescence Assays"
J. Am. Chem. Soc. 2005, 127, 13293-13299.

7.
Patrick J. Hrdlicka, T. Santhosh Kumar and Jesper Wengel.*
"Targeting of Mixed Sequence Double-Stranded DNA Using Pyrene-Functionalized 2'-Amino-?-L-LNA"
Chem. Commun. 2005, 4279-4281.

6.
B. Ravindra Babu, Patrick J. Hrdlicka, Christine J. McKenzie and Jesper Wengel.*
"Optimized DNA Targeting Using N,N-Bis(2-pyridylmethyl)-β-alanyl 2’-Amino-LNA"
Chem. Commun. 2005, 1705-1707.

5.
B. Ravindra Babu, Raunak, Mads D. Sørensen, Patrick J. Hrdlicka, Smriti Trikha, Ashok K. Prasad, Virinder S. Parmar and Jesper Wengel.*
"Novel Nucleic Acid Architectures Involving LNA (Locked Nucleic Acid) and Pyrene Residues – Results from an Indo-Danish Collaboration"
Pure Appl. Chem. 2005, 77, 319–326.

4.
Patrick J. Hrdlicka, Nicolai K. Andersen, Jan S. Jepsen, Flemming G. Hansen, Kim F. Haselmann, Claus Nielsen and Jesper Wengel.*
"Synthesis and Biological Evaluation of Branched and Conformationally Restricted Analogs of the Anticancer Compounds 3'-C-Ethynyluridine (EUrd) and 3'-C-Ethynylcytidine (ECyd)"
Bioorg. Med. Chem. 2005, 13, 2597-2621.

3.
Patrick J. Hrdlicka, Jan S. Jepsen, Claus Nielsen and Jesper Wengel.*
"Synthesis and Biological Evaluation of Nucleobase-modified Analogs of the Anticancer Compounds 3'-C-Ethynyluridine (EUrd) and 3'-C-Ethynylcytidine (ECyd)"
Bioorg. Med. Chem. 2005, 13, 1249–1260.

2.
Patrick J. Hrdlicka, B. Ravindra Babu, Mads D. Sørensen and Jesper Wengel.*
"Interstrand Communication Between 2'-N-(Pyren-1-yl)methyl-2'-amino LNA Monomers in Nucleic Acid Duplexes"
Chem. Commun. 2004, 1478–1479.

1.
Patrick J. Hrdlicka, Anders B. Sørensen, Bjarne R. Poulsen, George J. G. Ruijter, Jaap Visser and Jens J. L. Iversen.*
"Characterization of Nerolidol Biotransformation Based on Indirect On-Line Estimation of Biomass Concentration and Physiological State in Batch Cultures of Aspergillus niger"
Biotechnol. Prog. 2004, 20, 368–376.