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Chemistry Department Homepage >> Faculty >> Eriks Rozners

Eriks Rozners
Associate Professor
Organic and Bioorganic Chemistry

Department of Chemistry
State University of New York at Binghamton
Binghamton, NY 13902-6000

Email:

erozners@binghamton.edu

Office:

Science II 315

Phone:

(607) 777-2441

Fax:

(607) 777-4478

Professional Background

Research Interests

Our research interests are in the chemistry and biochemistry of nucleic acids with a focus on elucidation of RNA’s structure and function. The research philosophy is to use organic chemistry as the enabling discipline to create unique model systems and tools for fundamental studies and practical applications in nucleic acid biochemistry, biophysics and biomedicine. The current projects include design, synthesis, and biophysical exploration of RNA analogs having non-phosphorous internucleoside linkages and development of novel RNA binders for biomedical applications.

Amide-Linked RNA Analogues

Recent discovery of RNA interference (RNAi) has revitalized the idea of gene therapy using short synthetic oligonucleotides. The long-term goal of this project is to develop amides 1 and 2 (Figure 1) as neutral and hydrophobic mimics of the phosphodiester linkages in RNA and potentially useful modifications for therapeutic applications of short interfering RNAs (siRNAs). Amide linkages may offer several advantages for siRNAs. First, the absence of the natural phosphate will confer high nuclease resistance to such RNA analogues. Second, the reduction of the negative charge may facilitate crossing of cellular membranes. Third, the increased hydrophobicity may favor binding to serum transport proteins, which would improve the biodistribution and pharmacokinetics of the modified siRNAs.

The specific aims are to:

  1. Develop solid-phase synthesis of amide-linked RNA.
  2. Confirm that amide-linked RNA can mimic the secondary structure of natural RNA using spectroscopic (UV melting and CD) and X-ray crystallographic techniques.
  3. Probe the effect of amide modifications on cellular uptake and activity of siRNAs.

If accepted by RNAi machinery, amide modifications may significantly improve the properties of synthetic siRNAs and may find broad applications ranging from fundamental research on RNA structure and RNAi mechanism to rational drug development. Mimicking the phosphate backbone using amides will also advance fundamental knowledge on how chemical modifications influence RNA’s conformation, hydration, and thermal stability. Such a knowledge will be important for rational engineering of the desired structural and biological properties in nucleic acid analogues for a wide variety of applications.

Sequence Selective Recognition of RNA

There is an urgent need to develop new drugs to combat infectious, genetic and neurodegenerative diseases. The central role that non-coding RNAs play in gene expression makes them attractive novel drug targets. The long-term goals of this project are to (1) explore new modes of sequence selective RNA recognition and (2) develop novel compounds that modulate RNA’s structure and function. This is important for design of broad range of novel RNA targeting therapeutics, such as antibacterial, antiviral and anticancer compounds. Most of the known RNA binding drugs combination of hydrophobic (stacking and intercalation) and electrostatic (charge-charge attraction) interactions to achieve shape selective recognition. Whereas many compounds exhibit high binding affinity, the selectivity of the above interactions is typically low. A third binding mode, hydrogen bond mediated sequence selective binding into the major groove of RNA is typically underutilized in current drug design.

We propose that Peptide Nucleic Acid derivatives (Figure 2, PNA) conjugated to positively charged ligands (polyamines and amino acids) will provide optimal affinity and selectivity for recognition and modulation of double helical and non-canonical RNA structures.

The specific aims are to:

  1. Study the affinity and sequence selectivity of triple helical binding of PNA to RNA double helices.
  2. Study the formation of strand displacement complexes between PNA and biologically important RNA structures.
  3. Study the ability of PNA to bind and modulate the secondary structure of complex therapeutically relevant double helical RNA motifs, such as the A-site of bacterial 16S rRNA.

This project explores new modes of sequence selective RNA recognition and is expected to lead to development of novel compounds that modulate RNA’s structure and function. The ultimate application of such compounds will be in design of novel antibacterial, antiviral and anticancer therapeutics, which in the era of alarming drug resistance is rapidly becoming a high priority objective.

Teaching Interests

Organic Chemistry

Selected Publications


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© Department of Chemistry, State University of New York at Binghamton, Binghamton, NY 13902-6000

Updated 5-12-10
by Vincent Sica