Colin J Suckling

• BSc PhD DSc
• Professor at University of Strathclyde

The inhibitory-kappaB kinases (IKKs) IKKα and IKKβ play central roles in regulating the non-canonical and canonical NF-κB signalling pathways. Whilst the proteins that transduce the signals of each pathway have been extensively characterised, the clear dissection of the functional roles of IKKα-mediated non-canonical NF-κB signalling versus IKKβ-dr...

Background Acanthamoeba spp. is the causative agent of Acanthamoeba keratitis and granulomatous amoebic encephalitis. Strathclyde minor groove binders (S-MGBs) are a promising new class of anti-infective agent that have been shown to be effective against many infectious organisms. Objectives To synthesize and evaluate the anti-Acanthamoeba activit...

ES‐62, a protein secreted by Acanthocheilonema viteae , is anti‐inflammatory by virtue of covalently attached phosphorylcholine (PC) residues and thus a library of drug‐like small molecule analogues (SMAs) based on its PC moieties has been designed for therapeutic purposes. Two members, SMAs 11a and 12b, were previously found to suppress production...

The challenges of bringing new medicines to patients have been extensively discussed and debated, including consideration of the contribution that academic laboratories can make. At the University of Strathclyde, drug discovery has been a continuing focal activity since the 1960s, and in the past 30 years, the author has led or contributed to many...

Treatment of Mycobacterium tuberculosis and Mycobacterium avium infections requires multiple drugs for long time periods. Mycobacterium protein-tyrosine-phosphatase B (MptpB) is a key M. tuberculosis virulence factor that subverts host antimicrobial activity to promote intracellular survival. Inhibition of MptpB reduces the infection burden in vivo...

Mice develop pathology in the lungs as they age and this may be accelerated by a high calorie diet (HCD). ES-62 is a protein secreted by the parasitic worm Acanthocheilonema viteae that is immunomodulatory by virtue of covalently attached phosphorylcholine (PC) moieties. In this study, we show that weekly treatment of C57BL/6J mice with ES-62 prote...

MGB-BP-3 is a potential first-in-class antibiotic, a Strathclyde Minor Groove Binder (S-MGB), that has successfully completed Phase IIa clinical trials for the treatment of Clostridioides difficile associated disease. Its precise mechanism of action and the origin of limited activity against Gram-negative pathogens are relatively unknown. Herein, t...

The neglected tropical disease leishmaniasis, caused by Leishmania spp., is becoming more problematic due to the emergence of drug-resistant strains. Therefore, new drugs to treat leishmaniasis, with novel mechanisms of action, are urgently required. Strathclyde minor groove binders (S-MGBs) are an emerging class of anti-infective agent that have b...

Quantitative drug imaging in live cells is a major challenge in drug discovery and development. Many drug screening techniques are performed in solution, and therefore do not consider the impact of the complex cellular environment in their result. As such, important features of drug-cell interactions may be overlooked. In this study, Raman microsco...

Despite significant increases in human lifespan over the last century, adoption of high calorie diets (HCD) has driven global increases in type-2 diabetes, obesity and cardiovascular disease, disorders precluding corresponding improvements in healthspan. Reflecting that such conditions are associated with chronic systemic inflammation, evidence is...

The standard drug discovery paradigm of single molecule – single biological target – single biological effect is perhaps particularly unsuitable for anti-infective drug discovery. This is due to the rapid evolution of resistance likely to be observed with single target drugs. Multitargeted anti-infective drugs are likely to be superior due to their...

The immunomodulatory property of some parasitic helminths is well documented. The glycoprotein ES-62 from the nematode, acanthocheilonema viteae has been found to possess immunomodulatory properties. Two small molecule analogues (SMA's) of ES-62 (S3 and S5) were found to mimic its immunomodulatory properties in vivo and were active in animal models...

Background Previously, we evaluated the intracellular mycobactericidal activity of the minor groove binder, S-MGB-364 against the clinical Mycobacterium tuberculosis (Mtb) strain HN878 in macrophages. Objectives To assess the mycobactericidal activity of S-MGB-364 in Mtb-infected mice. Further, we investigated a plausible DNA binding mechanism of...

Correction for ‘Truncated S-MGBs: towards a parasite-specific and low aggregation chemotype’ by Daniel P. Brooke et al. , RSC Med. Chem. , 2021, 12 , 1391–1401, DOI: 10.1039/D1MD00110H.

ES-62 is the major secreted protein of the parasitic filarial nematode, Acanthocheilonema viteae. The molecule exists as a large tetramer (MW, ~240kD), which possesses immunomodulatory properties by virtue of multiple phosphorylcholine (PC) moieties attached to N-type glycans. By suppressing inflammatory immune responses, ES-62 can prevent disease...

The immunomodulatory property of some parasites is well documented. Their potential for development of therapeutic agents for diseases of the immune system has also been explored. The glycoprotein ES-62 from the nematode, Acanthocheilonema viteae was found to possess immunomodulatory properties. Two small molecule analogues (SMA’s) of ES-62 were fo...

This paper describes the design and synthesis of Strathclyde minor groove binders (S-MGBs) that have been truncated by the removal of a pyrrole ring in order to mimic the structure of the natural product, disgocidine. S-MGBs have been found to be active against many different organisms, however, selective antiparasitic activity is required. A panel...

Rising levels of antibiotic resistance dictate that new antibiotics with novel modes of action must be found. Here, we investigated the mode of action of a novel antibiotic that is a member of a family of synthetic DNA minor groove binding (MGB) molecules. MGB-BP-3 has successfully completed a Phase II clinical trial in humans as an orally administ...

Anti-infective and anticancer drugs share the serious problem that over time resistance develops to their effects leading to clinical obsolescence. Research at the University of Strathclyde has discovered a platform of anti-infective drugs based upon minor groove binders for DNA that have exceptional resilience to the development of resistance in t...

Decaprenylphosphoryl-β-D-ribose 2’-epimerase (DprE1) is an essential enzyme in Mycobacterium tuberculosis and has recently been studied as a potential drug target, with inhibitors progressing to clinical studies. Here we describe the identification of a novel series of morpholino-pyrimidine DprE1 inhibitors. These were derived from a phenotypic hig...

One of the most rapidly increasing human public health problems is obesity, whose sequelae like type-2 diabetes, represent continuously worsening, life-long conditions. Over the last 15 years, data have begun to emerge from human and more frequently, mouse studies, that support the idea that parasitic worm infection can protect against this conditi...

Traditional cytotoxic agents which act through a DNA-alkylating mechanism are relatively non-specific, resulting in a small therapeutic window and thus limiting their effectiveness. In this study, we evaluate a panel of 24 non-alkylating minor groove binders (MGBs), including 14 novel compounds, for in vitro anti-cancer activity against a human col...

Charles Walter Suckling (1920–2013) is most remembered for being the discoverer of the inhalant anaesthetic halothane, which revolutionized anaesthesia and surgical practice. He was born in Teddington, Middlesex, but grew up largely in Wallasey, Merseyside, where his father was a cargo superintendent for imports from Australia produced by one of Ch...

MGB-BP-3 (MGB) is a novel synthetic antibiotic inspired by Distamycin – a natural product that is capable of binding to the minor groove of DNA. MGB has a high bactericidal activity against a broad range of Gram-positive bacteria without the toxicity associated with the natural products that it was inspired by. Its oral formulation, developedfor th...

Acanthamoeba is a free-living amoeba widely distributed in the environment which exists as two stages in their life cycle: a motile and trophic replicating trophozoite and a resistant cyst stage. In recent years, the incidence of infections due to Acanthamoeba spp. has shown a remarkable increase. This parasite is the causative agent of a sight-thr...

Animal African trypanosomiasis (AAT) is a significant socioeconomic burden for sub-Saharan Africa due to its huge impact on livestock health. Existing therapies including those based upon Minor Groove Binders (MGBs), such as the diamidines, which have been used for decades, have now lost efficacy in some places due to the emergence of resistant par...

Parasitic helminths and their isolated secreted products show promise as novel treatments for allergic and autoimmune conditions in humans. Foremost amongst the secreted products is ES-62, a glycoprotein derived from Acanthocheilonema viteae, a filarial nematode parasite of gerbils, which is anti-inflammatory by virtue of covalently-attached phosph...

A series of 3-aryl(pyrrolidin-1-yl)butanoic acids were synthesized using a diastereoselective route, via a rhodium catalyzed asymmetric 1,4-addition of arylboronic acids in the presence of ( R)-BINAP to a crotonate ester to provide the ( S) absolute configuration for the major product. A variety of aryl substituents including morpholine, pyrazole,...

The immunomodulatory actions of parasitic helminth excretory-secretory (ES) products that serendipitously protect against development of chronic inflammatory disorders are well established: however, knowledge of the interaction between ES products and the host musculoskeletal system in such diseases is limited. In this study, we have focused on ES-...

Parasitic worms are receiving much attention as a potential new therapeutic approach to treating autoimmune and allergic conditions but concerns remain regarding their safety. As an alternative strategy, we have focused on the use of defined parasitic worm products and recently taken this one step further by designing drug-like small molecule analo...

ES-62 is a protein secreted by the parasitic worm Acanthocheilonema viteae that is anti-inflammatory by virtue of covalently attached phosphorylcholine. Previously we have reported that drug-like Small Molecule Analogues (SMAs) of its phosphorylcholine moiety can mimic ES-62 in protecting against disease development in certain mouse models of autoi...

Objectives: The slow development of major advances in drug discovery for the treatment of Mycobacterium tuberculosis ( Mtb ) infection suggests a compelling need for evaluation of more effective drug therapies against TB. New classes of drugs are constantly being evaluated for anti-mycobacterial activity with currently a very limited number of new...

IKKβ plays a central role in the canonical NF-kB pathway, which has been extensively characterised. The role of IKKα in the non-canonical NF-kB pathway, and indeed in the canonical pathway as a complex with IKKβ, is less well understood. One major reason for this is the absence of chemical tools designed as selective inhibitors for IKKα over IKKβ,...

ES-62, a glycoprotein secreted by the parasitic filarial nematode Acanthocheilonema viteae, subverts host immune responses towards anti-inflammatory phenotypes by virtue of covalently attached phosphorylcholine (PC). The PC dictates that ES-62 exhibits protection in murine models of inflammatory disease and hence a library of drug-like PC-based sma...

This study details the synthesis and biological evaluation of a collection of 19 structurally related Minor Groove Binders (MGBs), derived from the natural product distamycin, which were designed to probe antifungal and antimycobacterial activity. From this initial set, we report several MGBs that are worth more detailed investigation and optimisat...

The title nitro­pyrrole-based compounds, C7H8N2O4, (I) (ethyl 4-nitro-1H-pyrrole-2-carboxyl­ate), its derivative C12H14N2O4, (II) [ethyl 4-nitro-1-(4-pent­yn­yl)-1H-pyrrole-2-carboxyl­ate], C15H26N4O3, (III) {N-[3-(di­methyamino)prop­yl]-1-isopentyl-4-nitro-1H-pyrrole-2-carboxamide}, and C20H27N9O5, (IV) {1-(3-azido­prop­yl)-4-(1-methyl-4-nitro-1H-...

p300/CREB binding protein associated factor (PCAF/KAT2B) and general control non-derepressible 5 (GCN5/KAT2A) are multidomain proteins that have been implicated in retroviral infection, inflammation pathways and cancer development. However, outside of viral replication, little is known about the dependence of these effects on the C-terminal bromodo...

The stress-inducible transcription factor, NF-κB, plays an important in role in B-cell malignancies, regulating expression of a plethora of genes including those that drive proliferation, apoptosis and survival. Non-canonical ('alternative') NF-κB signalling, resulting in processing of the p100 subunit to p52 and dimerization with RelB, is less wel...

A series of 47 structurally diverse MGBs, derived from the natural product distamycin, was evaluated for anti-lung cancer activity by screening against the melanoma cancer cell line B16-F10. Five compounds have been found to possess significant activity, more so than a standard therapy, Gemcitabine. Moreover, one compound has been found to have an...

Figure S2. Effect of ES‐62 SMA 12b on cytokine production in the draining lymph nodes as measured by qRT‐PCR. qRT‐PCR analysis of IFN‐γ (a), IL‐1β (b), IL‐17A (c), IL‐4 (d), IL‐5 (e), IL‐13 (f) and Hmox (g) mRNA levels in the lungs of HDM mice treated with 12b either throughout the model (12b‐1), prophylactically at the sensitization only (12b‐1‐S)...

Figure S4. Effect of ES‐62 SMA 11a on cytokine production in the draining lymph nodes as measured by qRT‐PCR. qRT‐PCR analysis of IFN‐γ (a), IL‐1β (b), IL‐17A (c), IL‐4 (d), IL‐5 (e), IL‐13 (f) and Hmox (g) mRNA levels in the lungs of HDM mice untreated (“None”) or treated with 1 μg injections of 11a (“11a‐1”) throughout the model. The data are fro...

Figure S3. Effect of ES‐62 SMA 11a on cytokine production in the lungs as measured by qRT‐PCR. qRT‐PCR analysis of IFN‐γ (a), IL‐1β (b), IL‐17A (c), IL‐4 (d), IL‐5 (e), IL‐13 (f) and Hmox (g) mRNA levels in the lungs of HDM mice untreated (“None”) or treated with 1 μg injections of 11a (“11a‐1”) throughout the model. The data are from a single expe...

Figure S1. Schematic of HDM and CR models of airway hyper‐responsiveness. For the HDM model, C57BL/6 animals were treated intranasally with SMAs 11a or 12b (10, 1 and 0·1 μg/dose) 1 h prior to administration of HDM extract (1 or 10 μg/dose). The cockroach extract model utilized BALB/c animals that were treated with SMAs 11a or 12b (1 μg/dose) subcu...

Figure S5. Representative flow cytometric gating strategy for the CR extract model. For the flow cytometric phenotypic analysis, the cells of interest and exclusion of doublets were determined by the forward and side scatter parameters of the cellular populations (a, b). Siglec F was used to identify Eosinophils (c: SSChighSiglecF+), while a separa...

A set of 31 DNA minor groove binders (MGBs) with diverse structural features relating to both physical chemical properties and DNA binding sequence preference has been evaluated as potential drugs to treat Plasmodium falciparum infections using a chloroquine sensitive strain (3D7) and a chloroquine resistant strain (Dd2) in comparison with human em...

ES-62 is a glycoprotein secreted by the filarial nematode Acanthocheilonema viteae that protects against ovalbumin (OVA)-induced airway hyper-responsiveness in mice by virtue of covalently attached anti-inflammatory phosphorylcholine (PC) residues. We have recently generated a library of Small Molecule Analogues (SMAs) of ES-62 based around its act...

Inhibitors of mitochondrial branched chain aminotransferase (BCATm), identified using fragment screening, are described. This was carried out using a combination of STD-NMR, thermal melt (Tm) and biochemical assays to identify compounds that bound to BCATm, which were subsequently progressed to X-ray crystallography, where a number of exemplars sho...

Highlights • Minor Groove Binders (MGBs) possess activity against Trypanosma brucei brucei. • 5 MGBs have been identified as leads for future investigation, each with IC50 values lower than 40 nM. • DNA remains a possible target for these MGBs in trypanosomes, similar to the case for bacteria.

Following the discovery of cell penetrant pyridine-4-carboxylate inhibitors of the KDM4 (JMJD2) and KDM5 (JARID1) families of histone lysine demethylases (e.g., 1), further optimization led to the identification of non-carboxylate inhibitors derived from pyrido[3,4-d]pyrimidin-4(3H)-one. A number of exemplars such as compound 41 possess interesting...

Chronic asthma is associated with persistent lung inflammation and long-term remodelling of the airways that have proved refractory to conventional treatments such as steroids, despite their efficacy in controlling acute airway contraction and bronchial inflammation. As its recent dramatic increase in industrialised countries has not been mirrored...

The hybridisation of hits, identified by complementary fragment and high throughput screens, enabled the discovery of the first series of potent inhibitors of mitochondrial branched-chain aminotransferase (BCATm), based on a 2-benzylamino-pyrazolo[1,5-a]pyrimidinone-3-carbonitrile template. Structure-guided growth enabled rapid optimisation of acti...

Introduction ES-62, a phosphorylcholine (PC)-containing immunomodulator secreted by the parasitic worm Acanthocheilonema viteae, protects against nephritis in the MRL/Lpr mouse model of systemic lupus erythematosus (SLE). However, ES-62 is not suitable for development as a therapy and thus we have designed drug-like small molecule analogues (SMAs)...

In the crystal, the title compound, C12H19NO2S, has a disordered structure with two equally populated conformations of the amine fragment. A pair of weak C—H⋯O inter­molecular inter­actions between the CH2 and SO2 groups gives a one-dimensional supra­molecular structure that propagates through translation along the a-axis direction.

Rheumatoid arthritis (RA) remains a debilitating autoimmune condition as many patients are refractory to existing conventional and biologic therapies, and hence successful development of novel treatments remains a critical requirement. Towards this, we now describe a synthetic drug-like small molecule analogue, SMA-12b, of an immunomodulatory paras...

ES-62 is the major secreted protein of the rodent filarial nematode Acanthocheilonema viteae. The molecule contains covalently attached phosphorylcholine (PC) residues, which confer anti-inflammatory properties on ES-62, underpinning the idea that drugs based on this active moiety may have therapeutic potential in human diseases associated with abe...

In the crystal, the title compound, C12H19NO2S, has a disordered structure with two equally populated conformations of the amine fragment. A pair of weak C—H...O intermolecular interactions between the CH2 and SO2 groups gives a one-dimensional supramolecular structure that propagates through translation along the a-axis direction.

Riboswitches are conserved regions within mRNA molecules that bind specific metabolites and regulate gene expression. TPP-riboswitches, which respond to thiamine pyrophosphate (TPP), are involved in the regulation of thiamine metabolism in numerous bacteria. As these regulatory RNAs are often modulating essential biosynthesis pathways they have bec...

Solution-phase self-association characteristics and DNA molecular-recognition properties are reported for three close analogues of minor-groove-binding ligands from the thiazotropsin class of lexitropsin molecules; they incorporate isopropyl thiazole as a lipophilic building block. Thiazotropsin B (AcImPyiPrThDp) shows similar self-assembly charact...

The treatment of Human African Trypanosomiasis remains a major unmet health need in sub-Saharan Africa. Approaches involving new molecular targets are important and pteridine reductase 1 (PTR1), an enzyme that reduces dihydrobiopterin in Trypanosoma spp. has been identified as a candidate target and it has been shown previously that substituted pyr...

ES-62, a glycoprotein secreted by the filarial nematode Acanthocheilonema viteae, exhibits anti-inflammatory properties by virtue of covalently attached phosphorylcholine (PC) moieties. Screening of a library of ES-62 PC-based small molecule analogues (SMAs) revealed that two compounds, termed 11a and 12b, mirrored the helminth product both in inhi...

The nitric oxide synthase (NOS) dimer is stabilized by a Zn2+ ion coordinated to four symmetry related Cys residues exactly along the dimer 2-fold axis. Each of the two essential tetrahydrobiopterin (H4B) molecules in the dimer interacts directly with the heme, and each H4B molecule is about 15 Å from the Zn2+. We have solved the crystal structures...

The nitric oxide synthase (NOS) dimer is stabilized by a Zn ²⁺ ion coordinated to symmetry related Cys residues exactly on the dimer axis. Each of the two essential tetrahydrobiopterin (H 4 B) molecules in the dimer interacts directly with the heme, and each H 4 B molecule is about 12 Å from the Zn ²⁺ . We have solved the crystal structures of the...

In spite of increasing evidence that parasitic worms may protect humans from developing allergic and autoimmune diseases, and the continuing identification of defined helminth-derived immunomodulatory molecules, to date no new anti-inflammatory drugs have been developed from these organisms. We have approached this matter in a novel manner by synth...

An antibacterial DNA minor groove binder is shown by NOE experiments to self-associate in aqueous solution at temperatures up to 80 C in an anti-parallel, head-to-tail orientation as found in binding to duplex DNA oligomers.