Dr Nicola Howarth

Lecturer

+44 131 4518026

n.m.howarth@hw.ac.uk


WP2.08

Heriot-Watt University

Edinburgh

EH14 4AS

http://www.eps.hw.ac.uk/departments/chemistry/nmh.htm

Biography


Dr. Nicola Howarth has considerable experience in the fields of medicinal and biological chemistry. Her principal research interests lie in the development of novel therapeutic agents for potential use in the treatment of cancer, HIV-1 and bacterial infections.


Her other research interests include the development of:


-novel nucleic acid biosensors

-new photoactivatable fluorescent probes for super-resolution microscopy

-new in vitro methods for determining key pharmacological parameters of pharmaceutical drugs (e.g. log P, permeability, etc).

Projects


DNA-binding ligands


The ability to selectively modulate gene expression will make a major impact in the treatment of a variety of human diseases. Our approach centres on the development of ligands which will bind to DNA in a sequence-selective manner so as to inhibit transcription. The majority of our research in this area is focused on the design and synthesis of novel DNA analogues in which the original sugar-phosphate backbone has been replaced by a peptide backbone.


Anti-HIV-1 agents


Despite the success of HAART, AIDS remains one of the most urgent world health problems. The therapeutic situation is challenged by rapid emergence of drug resistant strains and so new anti-HIV drugs are needed. We have recently identified a novel family of non-nucleoside reverse transcriptase inhibitors (NNRTIs) exemplified by N2-benzyloxycarbonylguan-9-yl acetic acid derivatives. These compounds were found to be less sensitive to common drug-resistant mutant strains than known NNRTIs.


Nucleic acid biosensors


The ability to identify particular nucleic acid sequences, both quickly and precisely, has become of increasing importance in recent years. We have embarked on a project to develop a novel colourimetric biosensor in which peptide nucleic acid (PNA)-functionalised lipids are incorporated into polydiacetylene (PDA) liposomes; the PNA is the detector and PDA the sensor. It is envisaged that when PNA binds to its target gene, PDA will be induced to change colour from blue to red.


Photoactivatable fluorescent probes


Until recently, fluorescence microscopy in biological and pharmacological research was limited in resolution by the physical properties of light and diffraction. However, with the advent of super-resolution microscopy, this barrier has been overcome permitting the visualisation and quantitation of cellular processes down to the single molecule level. This project is concerned with the development of new synthetic photoactivatable fluorescent probes for use in the technique of photoactivation localisation microscopy (PALM). This technique allows the observation of single protein molecules, with an accuracy in the order of 10 nm. At present this is only achievable using encodable fluorescent probes (e.g. Green Fluorescent Protein).


(in collaboration with Colin Rickman, IB3)


Permeability assays


This project concerns the development of novel methods for determining important physicochemical properties of pharmaceutical drugs, such as pKa and partition coeffient log P. More recently, we have embarked upon the development of a method for determining the dissolution rates and permeabilities of active pharmaceutical ingredients. These two parameters will allow us to predict, and hopefully simulate, the absorption of a pharmaceutical drug in the body.


(in collaboration with Dr Arno Kraft, ICS)

Group Members


Robert Ferguson

Alicja Graczyk