Engineering Subtype Selective Inhibitors Of Voltage-sensitive Sodium Channels
Funder
National Health and Medical Research Council
Funding Amount
$406,980.00
Summary
During efforts to find new inhibitors of voltage sensitive sodium channels (VSSCs), we have discovered two new families of mu-conotoxins from Australian Conus tulipa and C. striatus that inhibit neuronal and muscle forms of the tetrodotoxin-sensitive (TTX-S) sodium channel. From these and related analogues we have identified a number of selective and highly potent inhibitors of VSSCs, opening the possibility of producing the first subtype selective TTX-S inhibitors useful in diseases such as epi ....During efforts to find new inhibitors of voltage sensitive sodium channels (VSSCs), we have discovered two new families of mu-conotoxins from Australian Conus tulipa and C. striatus that inhibit neuronal and muscle forms of the tetrodotoxin-sensitive (TTX-S) sodium channel. From these and related analogues we have identified a number of selective and highly potent inhibitors of VSSCs, opening the possibility of producing the first subtype selective TTX-S inhibitors useful in diseases such as epilepsy and stroke. These analogues also showed high selectivity for TTX-S sodium channels over a TTX-resistant (TTX-R) subtype hPN3, a key channel involved in the transmission of neuropathic pain that we recently cloned from human dorsal root ganglia. Given that TTX-S and TTX-R sodium channels have the same overall structure but differ at a relatively small number of key positions likely to affect mu-conotoxin binding, we believe it is possible to reverse engineer mu-conotoxin pharmacology in favour of the TTX-R form. This project will engineer subtype specific inhibitors of sodium channels in nerves through an understanding of how and wheremu-conotoxin bind to the sodium channel. Our long-term goal is to produce sodium channel drug candidates using m-conotoxins as templates for the development of subtype selective inhibitors of TTX-S and TTX-R sodium channels. The results of this study are designed to maximise the potential of this class of peptides as leads to the development of a new classes of therapeutics for pain, epilepsy and stroke.Read moreRead less
Development Of Novel Antibacterial Compounds From Subtilosin A
Funder
National Health and Medical Research Council
Funding Amount
$490,724.00
Summary
We aim to overcome a problem that is not being addressed by pharmaceutical companies- i.e., there is an urgent need to develop new classes of antibacterial drugs because of the increasing prevalence of drug resistant bacteria. We will combine genetics, structural biology and chemistry to develop a new class of anti-bacterial drug based on a naturally occurring microbial molecule that is novel in structure and very stable- attributes that make it very different to existing therapeutic approaches.
The Structural Basis Of The Interaction Of Human Relaxins With Their Receptors.
Funder
National Health and Medical Research Council
Funding Amount
$573,807.00
Summary
Relaxin is a peptide that is involved in the regulation of the birth process. It has considerable promise as an anti-fibrotic agent. Recently, another relaxin-like peptide, relaxin-3, was identified and shown to be brain-specific. It modulates the stress response and appetite. Both relaxins act upon different receptors to elicit their biological effects. To exploit their clinical potential, we will determine how these peptides selectively bind and ativate their individual receptors.