Prof
Philip Keith MooreProfile page
Emeritus Professor
Pharmacology
- Emeritus ProfessorPharmacology
RESEARCH INTERESTS
Statement
I have maintained an active interest in research over many years (list of publications appended). Throughout this period, the underlying goal of my research has been to study the biosynthesis, catabolism and pharmacological effects of local hormones with specific reference to the identification and/or utilisation of drugs which interfere with these processes and the application of such drugs as 'tools' with which to probe the biological roles of these mediators. The primary focus of the work has been on the effect of mediators on the cardiovascular system and inflammation.
I am a Highly Cited author (ISI Web of Science).
Recent research emphasis
Recent research has centered on the possible physiological roles of alternative gaseous mediators (e.g. hydrogen sulphide, sulphur dioxide) in the cardiovascular system with special reference to their role(s) as putative inflammatory mediators. At NUS I set up a multi-disciplinary, multi-Faculty and multi-institutional project under my direct control (both scientific, managerial and financial) and involving in excess of 50 individuals (PIs, research staff and postgraduate students).
To date, work has concentrated on animal models of cardiovascular disease (myocardial infarction, septic, endotoxic and haemorrhagic shock, inflammatory disease - including pancreatitis, arthritis and wound healing). Physiological changes, determined using classical organ bath techniques, in vivo measurement of cardiovascular parameters in both anaesthetized and conscious (telemetry, intravital microscopy) animals, are correlated with biochemical events (direct measurement of plasma and tissue H2S levels, characterization of H2S synthesizing activity in tissue homogenates and assessment of the enzyme inhibitory effect of a range of drugs) using a variety of biochemical and molecular biological (e.g. blotting for enzymes which synthesise H2S [cystathionine b synthetase and cystathionine g lyase]) approaches.
Links were developed with key personnel in the Departments of Medicine and Surgery at the nearby National University Hospital (NUH) who provided human blood vessels for organ bath experiments and blood samples from patients with cardiovascular disease. To date, a blood bank (of approx 100 samples) has been put together (mostly patients with ongoing septic shock, immediate post myocardial infarction). Samples were utilised for measurement of H2S and other gaseous mediators. The mechanism of action of H2S on vascular and cardiac muscle is also being evaluated using a patch clamp approach (putative target is the KATP channel) and biochemically (effects on cyclic nucleotides, intracellular calcium etc). Preliminary experiments suggested roles for H2S in different models of inflammation as well as cell death and differentiation. International collaborations (Professor YC Zhu, Fudan University, Shanghai, China, Professor Y Yan, Xiamen University, China and Professor C Thiemermann, William Harvey Research Institute, London) have been developed and are active. Several collaborations with the pharmaceutical industry (Pfizer UK, NicOx Ltd., Italy and AltaPharm Ltd., Canada) are on-going.
Part of this work involved the development and biological characterization of novel H2S donor drugs. These included H2S-releasing diclofenac (S-diclofenac) as well as GYY4137. This latter compound was chemically synthesized as a result of a collaboration with Dr. Tan Choon-Hong (Department of Chemistry, NUS) and forms part of a programme dedicated to the process of new drug discovery based an effect on the endogenous L-cysteine:H2??S pathway.
At King's (2007-2-1) I continued this research effort. My research remains centred on the biology of H2S but has now expanded to include effects on ageing, asthma and atherosclerosis in collaboration with Dr S Sturzenbaum and Professor C Page (Pharmaceutical Science Division) and Professor A. Smith (Unit of Academic Surgery, St. Thomass Hospital). Based on previous work conducted in NUS I retain a strong interest in the possible effect of H2S on cancer/tumour growth. In addition, I am also very interested in the relationship between H2S and other gaseous biologically active molecules including NO and CO. Recently I have developed an interest in the role of H2S in ageing using C. elegans as a model organism and in the unexplored area of drug modulation of macrophage phenotype and function with a view to identifying completely new approaches to the treatment of inflammation and cancer.
On my return to NUS in October 2010 I initiated further research to evalauet the biological roles of H2S in various body systems. Ongoing collaborative work has established that H2S is an important regulator of ageing in C. elegans and work is continuing also to established the role of this gas in tumour development. Novel enzymes which synthesise H2S are also under evaluation using a variety of pharmacological and molecular biological means and efforts to develop novel drugs based on the H2S system have been stepped up.
Previous research summary of major achievements
(a) The identification of L-NG nitro arginine: This arginine analogue is a potent inhibitor of endothelium-dependent relaxation of blood vessels and thus nitric oxide synthase [NOS] (Moore et al., Br. J. Pharmacol. 99 408-412, 1990). L-NG nitro arginine has subsequently become the NOS inhibitor of choice in research laboratories world-wide (to date; 11,829 papers make reference to the compound) and has been used to probe the biological roles of NO in numerous mammalian and non-mammalian systems. Currently, the above paper has been cited >1000 times in the literature.
(b) The role of NO in pain perception: The finding that L-NG nitro arginine exhibited potent antinociceptive activity in the conscious mouse (Moore et al., Br. J. Pharmacol. 102 198-202, 1991) raised, for the first time, the possibility that NO may have a role to play in pain perception and was thus instrumental in 'opening' an entirely new field of NO research. This original observation has subsequently been confirmed by a number of other research groups and is now supported by a variety of electrophysiological, behavioural and biochemical markers for nociception in different species. Currently, the above paper has been cited >400 times in the literature.
(c) Identification of selective inhibitors of neuronal NOS (nNOS) with potential therapeutic application: Over the last 6 years this group has identified and introduced into the literature two novel compounds; 7-nitro indazole (7-NI; Moore et al., Br. J. Pharmacol. 108, 296-297, 1993) and 1,2 trifluoromethylphenyl imidazole (TRIM; Moore et al., Br. J. Pharmacol. 119, 423-431, 1997). Both of these compounds show selectivity for inhibition of the neuronal isoform of NOS thus exhibiting potent antinociceptive activity but without cardiovascular side effects. 7-NI, in particular, has found widespread use as an experimental tool with which to evaluate the biological effects of neurone-derived nitric oxide (to date; 389 papers make reference to the compound) and has been instrumental in identifying potential new clinical targets for this class of drug. The nNOS inhibitory effect of 7-NI and related indazole compounds was the subject of a patent application by Glaxo-Wellcome (in conjunction with KCL Enterprise) in 1997.
I have maintained an active interest in research over many years (list of publications appended). Throughout this period, the underlying goal of my research has been to study the biosynthesis, catabolism and pharmacological effects of local hormones with specific reference to the identification and/or utilisation of drugs which interfere with these processes and the application of such drugs as 'tools' with which to probe the biological roles of these mediators. The primary focus of the work has been on the effect of mediators on the cardiovascular system and inflammation.
I am a Highly Cited author (ISI Web of Science).
Recent research emphasis
Recent research has centered on the possible physiological roles of alternative gaseous mediators (e.g. hydrogen sulphide, sulphur dioxide) in the cardiovascular system with special reference to their role(s) as putative inflammatory mediators. At NUS I set up a multi-disciplinary, multi-Faculty and multi-institutional project under my direct control (both scientific, managerial and financial) and involving in excess of 50 individuals (PIs, research staff and postgraduate students).
To date, work has concentrated on animal models of cardiovascular disease (myocardial infarction, septic, endotoxic and haemorrhagic shock, inflammatory disease - including pancreatitis, arthritis and wound healing). Physiological changes, determined using classical organ bath techniques, in vivo measurement of cardiovascular parameters in both anaesthetized and conscious (telemetry, intravital microscopy) animals, are correlated with biochemical events (direct measurement of plasma and tissue H2S levels, characterization of H2S synthesizing activity in tissue homogenates and assessment of the enzyme inhibitory effect of a range of drugs) using a variety of biochemical and molecular biological (e.g. blotting for enzymes which synthesise H2S [cystathionine b synthetase and cystathionine g lyase]) approaches.
Links were developed with key personnel in the Departments of Medicine and Surgery at the nearby National University Hospital (NUH) who provided human blood vessels for organ bath experiments and blood samples from patients with cardiovascular disease. To date, a blood bank (of approx 100 samples) has been put together (mostly patients with ongoing septic shock, immediate post myocardial infarction). Samples were utilised for measurement of H2S and other gaseous mediators. The mechanism of action of H2S on vascular and cardiac muscle is also being evaluated using a patch clamp approach (putative target is the KATP channel) and biochemically (effects on cyclic nucleotides, intracellular calcium etc). Preliminary experiments suggested roles for H2S in different models of inflammation as well as cell death and differentiation. International collaborations (Professor YC Zhu, Fudan University, Shanghai, China, Professor Y Yan, Xiamen University, China and Professor C Thiemermann, William Harvey Research Institute, London) have been developed and are active. Several collaborations with the pharmaceutical industry (Pfizer UK, NicOx Ltd., Italy and AltaPharm Ltd., Canada) are on-going.
Part of this work involved the development and biological characterization of novel H2S donor drugs. These included H2S-releasing diclofenac (S-diclofenac) as well as GYY4137. This latter compound was chemically synthesized as a result of a collaboration with Dr. Tan Choon-Hong (Department of Chemistry, NUS) and forms part of a programme dedicated to the process of new drug discovery based an effect on the endogenous L-cysteine:H2??S pathway.
At King's (2007-2-1) I continued this research effort. My research remains centred on the biology of H2S but has now expanded to include effects on ageing, asthma and atherosclerosis in collaboration with Dr S Sturzenbaum and Professor C Page (Pharmaceutical Science Division) and Professor A. Smith (Unit of Academic Surgery, St. Thomass Hospital). Based on previous work conducted in NUS I retain a strong interest in the possible effect of H2S on cancer/tumour growth. In addition, I am also very interested in the relationship between H2S and other gaseous biologically active molecules including NO and CO. Recently I have developed an interest in the role of H2S in ageing using C. elegans as a model organism and in the unexplored area of drug modulation of macrophage phenotype and function with a view to identifying completely new approaches to the treatment of inflammation and cancer.
On my return to NUS in October 2010 I initiated further research to evalauet the biological roles of H2S in various body systems. Ongoing collaborative work has established that H2S is an important regulator of ageing in C. elegans and work is continuing also to established the role of this gas in tumour development. Novel enzymes which synthesise H2S are also under evaluation using a variety of pharmacological and molecular biological means and efforts to develop novel drugs based on the H2S system have been stepped up.
Previous research summary of major achievements
(a) The identification of L-NG nitro arginine: This arginine analogue is a potent inhibitor of endothelium-dependent relaxation of blood vessels and thus nitric oxide synthase [NOS] (Moore et al., Br. J. Pharmacol. 99 408-412, 1990). L-NG nitro arginine has subsequently become the NOS inhibitor of choice in research laboratories world-wide (to date; 11,829 papers make reference to the compound) and has been used to probe the biological roles of NO in numerous mammalian and non-mammalian systems. Currently, the above paper has been cited >1000 times in the literature.
(b) The role of NO in pain perception: The finding that L-NG nitro arginine exhibited potent antinociceptive activity in the conscious mouse (Moore et al., Br. J. Pharmacol. 102 198-202, 1991) raised, for the first time, the possibility that NO may have a role to play in pain perception and was thus instrumental in 'opening' an entirely new field of NO research. This original observation has subsequently been confirmed by a number of other research groups and is now supported by a variety of electrophysiological, behavioural and biochemical markers for nociception in different species. Currently, the above paper has been cited >400 times in the literature.
(c) Identification of selective inhibitors of neuronal NOS (nNOS) with potential therapeutic application: Over the last 6 years this group has identified and introduced into the literature two novel compounds; 7-nitro indazole (7-NI; Moore et al., Br. J. Pharmacol. 108, 296-297, 1993) and 1,2 trifluoromethylphenyl imidazole (TRIM; Moore et al., Br. J. Pharmacol. 119, 423-431, 1997). Both of these compounds show selectivity for inhibition of the neuronal isoform of NOS thus exhibiting potent antinociceptive activity but without cardiovascular side effects. 7-NI, in particular, has found widespread use as an experimental tool with which to evaluate the biological effects of neurone-derived nitric oxide (to date; 389 papers make reference to the compound) and has been instrumental in identifying potential new clinical targets for this class of drug. The nNOS inhibitory effect of 7-NI and related indazole compounds was the subject of a patent application by Glaxo-Wellcome (in conjunction with KCL Enterprise) in 1997.