Kevin D Read

• University of Dundee

In this article, we detail our latest findings towards developing diversified series of potential non-hormonal contraceptive compounds using a phenotypic screening approach against human sperm. Phenotypic screening of nine compound libraries (88,773 compounds in total) was conducted using an in-house automated robotic screening platform, allowing q...

The vast majority of clinical small molecule multi-kinase inhibitors (mKI) report abject failures in targeting cancers with high stem cell contents like high-grade glioma and colorectal cancers. The FDA-approved mKIs to date ablate receptor tyrosine kinase signaling but do not target the paradoxical WNT signaling which is a key survival driver for...

Bifunctional targeted protein degraders, also known as Proteolysis Targeting Chimeras (PROTACs), are an emerging drug modality that may offer a new approach to understand and treat neurodegenerative diseases. These molecules have a non-occupancy based, sub-stoichiometric mechanism of action which results in removal of target proteins from cells, pr...

Although not currently in the infectious disease spotlight, there is still a pressing need for new agents to treat tuberculosis caused by Mycobacterium tuberculosis. As there is an ever-increasing amount of clinical resistance to the current drugs, ideally new drugs would be found against novel targets to circumvent pre-existing resistance. A pheno...

Male contraceptive options and infertility treatments are limited, and almost all innovation has been limited to updates to medically assisted reproduction protocols and methods. To accelerate the development of drugs that can either improve or inhibit fertility, we established a small molecule library as a toolbox for assay development and screeni...

A key step in drug discovery, common to many disease areas, is preclinical demonstration of efficacy in a mouse model of disease. However, this demonstration and its translation to the clinic can be impeded by mouse-specific pathways of drug metabolism. Here, we show that a mouse line extensively humanized for the cytochrome P450 gene superfamily (...

The emergence of new synthetic cannabinoid receptor agonists (SCRAs) onto the illicit drugs market continues to cause harm, and the overall availability of physicochemical and pharmacokinetic data for new psychoactive substances is lacking. The lipophilicity of 23 SCRAs and the plasma protein binding (PPB) of 11 SCRAs was determined. Lipophilicity...

There is an urgent need for new tuberculosis (TB) treatments, with novel modes of action, to reduce the incidence/mortality of TB and to combat resistance to current treatments. Through both chemical and genetic methodologies, polyketide synthase 13 (Pks13) has been validated as essential for mycobacterial survival and as an attractive target for M...

We have adapted the cell painting assay developed by Carpenter and colleagues on cultured U2OS cells to human spermatozoa. In Sperm Cell Painting (SCP) we assemble an image-based quantitative fingerprint of the functional state of sperm. We use this assay to gain insight into the mechanism of action of compounds that modify sperm function and as a...

There is an urgent need for new treatments for Chagas disease, a parasitic infection which mostly impacts South and Central America. We previously reported on the discovery of GSK3494245/DDD01305143, a preclinical candidate for visceral leishmaniasis which acted through inhibition of the Leishmania proteasome. A related analogue, active against Try...

Working in drug discovery is difficult for many institutions due to the need for resources, funding, and in-country expertise. The Wellcome Centre for Anti-Infective Research (WCAIR) is responding to the unmet training needs for individuals/institutions working in drug discovery in low-middle income countries. Through their training program, indivi...

In September 2022, the Drug Discovery Unit at the University of Dundee, UK, organised an international meeting at the Wellcome Collection in London to explore the current clinical situation and challenges associated with treating schistosomiasis. The aim of this meeting was to discuss the need for new treatments in view of the clinical situation an...

The synthesis and evaluation of twenty six new phenylurea substituted 2,4-diamino-pyrimidines against Plasmodium falciparum (Pf) 3D7 are reported. Compounds were prepared to improve both anti-malarial activity and selectivity of the series previously reported by our group. Additional properties have been determined to assess their potential as anti...

Tuberculosis is a major global cause of both mortality and financial burden mainly in low and middle-income countries. Given the significant and ongoing rise of drug-resistant strains of Mycobacterium tuberculosis within the clinical setting, there is an urgent need for the development of new, safe and effective treatments. Here the development of...

Leishmaniasis (visceral and cutaneous), Chagas disease and human African trypanosomiasis cause substantial death and morbidity, particularly in low- and middle-income countries. Although the situation has improved for human African trypanosomiasis, there remains an urgent need for new medicines to treat leishmaniasis and Chagas disease; the clinica...

There is a need for non-hormonal contraceptives. One area that needs further investigation is the development of male contraceptives. Comparatively little is understood about potential drug targets in men to achieve a reversible contraceptive effect. In this article, we review the need for male contraceptives and some thoughts around the characteri...

Chagas disease caused by the protozoan Trypanosoma cruzi is endemic to 21 countries in the Americas, effects approximately 6 million people and on average results in 12,000 deaths annually. Human African Trypanosomiasis (HAT) is caused by the Trypanosoma brucei sub-species, endemic to 36 countries within sub-Saharan Africa. Treatment regimens for t...

Approximately 6–7 million people around the world are estimated to be infected with Trypanosoma cruzi, the causative agent of Chagas disease. The current treatments are inadequate and therefore new medical interventions are urgently needed. In this paper we describe the identification of a series of disubstituted piperazines which shows good potenc...

African animal trypanosomiasis or nagana, caused principally by infection of the protozoan parasites Trypanosoma congolense and Trypanosoma vivax, is a major problem in cattle and other livestocks in sub-Saharan Africa. Current treatments are threatened by the emergence of drug resistance and there is an urgent need for new, effective drugs. Here,...

Study question: Can a high-throughput screening (HTS) platform facilitate male fertility drug discovery? Summary answer: An HTS platform identified a large number of compounds that enhanced sperm motility. What is known already: Several efforts to find small molecules modulating sperm function have been performed but none have used high-throug...

With increasing drug resistance in tuberculosis (TB) patient populations, there is an urgent need for new drugs. Ideally, new agents should work through novel targets so that they are unencumbered by preexisting clinical resistance to current treatments. Benzofuran 1 was identified as a potential lead for TB inhibiting a novel target, the thioester...

Study question: Can a high-throughput screening platform facilitate male fertility drug discovery? Summary answer: A high-throughput screening platform identified a large number of compounds that enhanced sperm motility. What is known already: Several efforts to find small molecules modulating sperm function have been performed but not using high-t...

Twenty eight new N²,N⁴-diphenylpyrimidine-2,4-diamines have been prepared in order to expand our understanding of the anti-malarial SAR of the scaffold. The aim of the study was to make structural modifications to improve the overall potency, selectivity and solubility of the series by varying the anilino groups attached to the 2- and 4-position. W...

There is an urgent need for new treatments for visceral leishmaniasis (VL), a parasitic infection which impacts heavily large areas of East Africa, Asia, and South America. We previously reported on the discovery of GSK3494245/DDD01305143 (1) as a preclinical candidate for VL and, herein, we report on the medicinal chemistry program that led to its...

In vitro pharmacokinetic studies were conducted on enantiomer pairs of twelve valinate or tert-leucinate indole and indazole-3-carboxamide synthetic cannabinoid receptor agonists (SCRAs) detected on the illicit drug market to investigate their physicochemical parameters and structure-metabolism relationships (SMRs). Experimentally derived Log D7.4...

With the emergence of multi-drug-resistant strains of Mycobacterium tuberculosis, there is a pressing need for new oral drugs with novel mechanisms of action. A number of scaffolds with potent anti-tubercular in vitro activity have been identified from phenotypic screening that appear to target MmpL3. However, the scaffolds are typically lipophilic...

Livestock diseases caused by Trypanosoma congolense, T. vivax and T. brucei, collectively known as nagana, are responsible for billions of dollars in lost food production annually. There is an urgent need for novel therapeutics. Encouragingly, promising antitrypanosomal benzoxaboroles are under veterinary development. Here, we show that the most ef...

Myristoylation, the N-terminal modification of proteins with the fatty acid myristate, is critical for membrane targeting and cell signaling. Because cancer cells often have increased N-myristoyltransferase (NMT) expression, NMTs were proposed as anti-cancer targets. To systematically investigate this, we performed robotic cancer cell line screens...

Phenotypic screening of a 900 compound library of antitubercular nitroimidazole derivatives related to pretomanid against the protozoan parasite Trypanosoma cruzi (the causative agent for Chagas disease) identified several structurally diverse hits with an unknown mode of action. Following initial profiling, a first proof-of-concept in vivo study w...

Myristoylation is the N-terminal modification of proteins with the fatty acid myristate. This process is mediated by two ubiquitously expressed N-myristoyltransferases, NMT1 and , and is critical for membrane targeting and cell signaling. Because NMT expression is increased in some cancers, we used three robotic screens to evaluate the potential of...

The development of a chemical series with oral efficacy against visceral leishmaniasis is described.

Visceral leishmaniasis (VL) is a parasitic infection that results in approximately 26,000 – 65,000 deaths annually. The available treatments are hampered by issues such as toxicity, variable efficacy and unsuitable dosing options. The need for new treatments is urgent and led to a collaboration between the Drugs for Neglected Diseases initiative (D...

Chagas disease is caused by the protozoan parasite Trypanosoma cruzi. It is endemic in South and Central America and recently has been found in other parts of the world, due to migration of chronically infected patients. The current treatment for Chagas disease is not satisfactory, and there is a need for new treatments. In this work, we describe t...

Exhibition Dates: 2/5/2019 - 31/8/2019 Venue: LifeSpace science art reserach gallery, School of Life Sciences, University of Dundee What would a parasite's travel blog look like? As the Wellcome Centre for Anti-Infectives Research (WCAIR) strives to create a new medicine to cure the deadly Leishmania, LifeSpace gallery has collaborated with artist...

In May 2019, the Wellcome Centre for Anti-Infectives Research (WCAIR) at the University of Dundee, UK, held an international conference with the aim of discussing some key questions around discovering new medicines for infectious diseases and a particular focus on diseases affecting Low and Middle Income Countries. There is an urgent need for new d...

O-GlcNAcylation is an abundant post-translational modification in the nervous system, linked to both neurodevelopmental and neurodegenerative disease. However, the mechanistic links between these phenotypes and site-specific O-GlcNAcylation remain largely unexplored. Here, we show that Ser517 O-GlcNAcylation of the microtubule-binding protein Colla...

N-myristoylation, the addition of the 14-carbon fatty acid to proteins, plays a fundamental role in cell signaling. Over 200 proteins are myristoylated, including the Src Family Kinases (SFK) Src, Lyn, Lck, Hck, and Fgr, as well as c-Abl, Gα subunits, caspase truncated (ct-) Bid and ct-PAK2, regulating cell growth and apoptosis. Human myristoylatio...

Dysregulation of the kynurenine pathway (KP) leads to imbalances in neuroactive metabolites associated with the pathogenesis of several neurodegenerative disorders, including Huntington's disease (HD). Inhibition of the enzyme kynurenine 3-monooxygenase (KMO) in the KP normalises these metabolic imbalances and ameliorates neurodegeneration and rela...

Herein we describe the optimization of a phenotypic hit against Plasmodium falciparum based on an aminoacetamide scaffold. This led to N‐(3‐chloro‐4‐fluorophenyl)‐2‐methyl‐2‐{[4‐methyl‐3‐(morpholinosulfonyl)phenyl]amino}propanamide (compound 28) with low‐nanomolar activity against the intraerythrocytic stages of the malaria parasite, and which was...

Treatment of aggressive lymphoma is toxic, expensive, and a substantial proportion of patients relapse and die. There is an urgent need for more effective treatments. Myristoylation is required for biological activity of >200 intracellular proteins. N-myristoyltransferases (NMTs) transfer the fatty acid myristate to N-terminal glycine residue; ther...

Visceral leishmaniasis (VL), caused by the protozoan parasites Leishmania donovani and Leishmania infantum , is one of the major parasitic diseases worldwide. There is an urgent need for new drugs to treat VL, because current therapies are unfit for purpose in a resource-poor setting. Here, we describe the development of a preclinical drug candidat...

Malaria and cryptosporidiosis, caused by apicomplexan parasites, remain major drivers of global child mortality. New drugs for the treatment of malaria and cryptosporidiosis, in particular, are of high priority; however, there are few chemically validated targets. The natural product cladosporin is active against blood- and liver-stage Plasmodium f...

In order to study the role of S1PRs in inflammatory skin disease, S1PR modulators are dosed orally and topically in animal models of disease. The topical application of S1PR modulators in these models may however lead to systemic drug concen-trations, which can complicate interpretation of the observed effects. We set out to design soft drug S1PR m...

The leishmaniases are diseases that affect millions of people across the world, in particular visceral leishmaniasis (VL) which is fatal unless treated. Current standard of care for VL suffers from multiple issues and there is a limited pipeline of new candidate drugs. As such, there is a clear unmet medical need to identify new treatments. This pa...

Crystallography has guided the hybridization of two series of Trypanosoma brucei N-myristoyltransferase (NMT) inhibitors, leading to a novel highly selective series. The effect of combining the selectivity enhancing elements from two pharmacophores is shown to be additive and has led to compounds that have greater than 1000-fold selectivity for TbN...

The structures of nifurtimox in Table 1 were incorrect and have been updated in the pdf and online. The authors apologize for any confusion caused.

Beta lactams represent perhaps the most important class of antibiotics yet discovered. However, despite many years of active research none of the currently approved drugs in this class combine oral activity with long duration of action. Recent devel-opments suggest that new beta lactam antibiotics with such a profile would have utility in the treat...

Chagas' disease, caused by the protozoan parasite Trypanosoma cruzi, affects 8-10 million people across the Latin American population and is responsible for around 12,500 deaths per annum. The current frontline treatments, benznidazole and nifurtimox, are associated with side effects and lack efficacy in the chronic stage of the disease, leading to...

Visceral leishmaniasis causes considerable mortality and morbidity in many parts of the world. There is an urgent need for the development of new, effective treatments for this disease. Here we describe the development of an anti-leishmanial drug-like chemical series based on a pyrazolopyrimidine scaffold. The leading compound from this series (7,...

The oral S1PR1 agonist ponesimod demonstrated substantial efficacy in a phase II clinical trial of psoriasis. Unfortunately, systemic side effects were observed, which included lymphopenia and transient bradycardia. We sought to develop a topical soft-drug S1PR1 agonist with an improved therapeutic index. By modifying ponesimod, we discovered an es...

With the emergence of multi-drug resistant strains of Mycobacterium tuberculosis there is a pressing need for new oral drugs with novel mechanisms of action. Herein, we describe the identification of a novel morpholino-thiophenes (MOT) series following phenotypic screening of the Eli Lilly corporate library against M. tuberculosis strain H37Rv. The...

Providing access to the data underlying research results in published literature allows others to reproduce those results or analyze the data in new ways. Health sciences librarians and information professionals have long been advocates of data sharing. It is time for us to practice what we preach and share the data associated with our published re...

Purpose: The detection of a novel psychoactive substance, 2F-MT-45, a fluorinated analogue of the synthetic opioid MT-45, was reported in a single seized tablet. MT-45, 2F-, 3F- and 4F-MT-45 were synthesised and reference analytical data were reported. The in vitro and in vivo metabolisms of MT-45 and 2F-MT-45 were investigated. Method: The refe...

Mycobacterium tuberculosis (MTb) possesses two non-proton pumping type II NADH dehydrogenase (NDH-2) enzymes which are predicted to be jointly essential for respiratory metabolism.. Furthermore, the structure of a closely related bacterial NDH-2 has been reported recently, allowing for the structure-based design of small-molecule inhibitors. Herein...

Recent development of benzoxaborole-based chemistry gave rise to a collection of compounds with great potential in targeting diverse infectious diseases, including human African Trypanosomiasis (HAT), a devastating neglected tropical disease. However, further medicinal development is largely restricted by a lack of insight into mechanism of action...

Phylogenetic analysis of ALDH family in Opisthokont. Each clade is labelled with the corresponding subfamily number. All human orthologues are highlighted in bold. The nodes with significant bootstrap value (>0.6) and Bayesian posterior probability (>90%) are indicated with stars. (PDF)

Metabolism profiles of T. brucei with the treatment of different benzoxaboroles. (PDF)

MS spectrums of AN3057, AN2861 and AN3057-derived metabolites from FBS-TbALDH3. (A) MS spectrums of the ion precursors from either AN3057 or the metabolite from AN3057+TbALDH3. The [M+H]+ ion at m/z 239.0 was identified with both, indicating no change in structure. (B) MS spectrums of the ions precursors from either AN2861 or the metabolites from A...

Synthesis of (4-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yloxy)phenyl)methanaminium chloride (AN3057). To the solution of 4-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yloxy)benzonitrile (1.2 g, 4.78 mmol) in EtOH (150 mL) under N2 was added Pd/C (10 wt.%, 0.178 g). The reaction mixture was hydrogenated for 26.5 h using a H2 balloon at room...

HPLC-MS analysis of AN3057-derived metabolites from MAOa- TbALDH3. (PDF)

HPLC-MS analysis of AN3054-derived metabolites from MAOa-TbALDH3. (A) HPLC peaks are indicated with corresponding retention time (RT), m/z of ion precursors identified in MS, and proposed structural formula. See S5 Fig for the detailed MS data. (B) MS spectrums of the ion precursors from either AN3054 or the metabolite from AN3054+TbALDH3. The [M+H...

Microdialysis device for binding the enzymatically generated TbALDH3 substrate. A 3.5 kDa dialysis membrane separates the two reservoirs allowing the diffusion of the benzaldehyde-benzoxaborole intermediate once formed by MaoA (lower reservoir) and subsequent binding by the catalytically inactive TbAlDH3 C259S mutant. (PDF)

Fo–Fc omit map contoured at 2.0 σ (green chicken wire) and interactions for NAD+ and the AN3057-aldehyde ligand bound to TbALDH3. All key residues are in stick representation, in which non-carbon atoms are marked in color, oxygen in red, nitrogen in blue, and phosphorus in orange. Potential hydrogen bonds are depicted as black dashed lines;; select...

Multiple sequence alignment of selected ALDHs. from T. brucei and H. sapiens (HsALDH3A1, P30838;; HsALDH3A2, P51648;; HsALDH3B1, P43353;; HsALDH3B2, P48448). Secondary structure elements are indicated for TbALDH3A2 (colored by domain: blue, catalytic domain; red, NAD-binding domain; green, oligomerisation domain) and HsALDH3A2 (colored in grey, fro...

Position of the gatekeeper helix. Structural superposition in cartoon representation of TbALDH3 (red) with HsALDH3A2 (grey) focussing on the gatekeeper helix and the conserved hydrogen bonding interaction (dashed line) between K481 and the backbone carbonyl of F474. (PDF)

Primers and constructs used in the work. (PDF)

Species, strains and protein acessions included in the phylogenetic analyses. (PDF)

Phylogenetic analysis of ALDH family in Trypanosomatida. Each clade is assigned in reference to the Opisthokont subfamilies, and labelled with the corresponding subfamily number identified with. The nodes with significant bootstrap value (>0.6) and Bayesian posterior probability (>90%) are indicated with stars. The family members in T. brucei are h...

MS spectrums of AN3057, AN2861 and AN3057-derived metabolites from MAOa-TbALDH3. (A) MS spectrums of the ion precursors from either AN3057 or the metabolite from AN3057+TbALDH3. The [M+H]+ ion at m/z 239.0 was identified with both, indicating no change in structure. (B) MS spectrums of the ions precursors from either AN2861 or the metabolites from...

TbALDH3 crystallography and refinement statistics. (PDF)

Allele-specific chemical genetics enables selective inhibition within families of highly-conserved proteins. The four BET (bromodomain & extra-terminal domain) proteins – BRD2, BRD3, BRD4 and BRDT bind acetylated chromatin via their bromodomains and regulate processes such as cell proliferation and inflammation. BET bromodomains are of particular i...

Background: REDCap, an electronic data capture tool, supports good research data management, but many researchers lack familiarity with the tool. While a REDCap administrator provided technical support and a clinical data management support unit provided study design support, a service gap existed. Case presentation: Librarians with REDCap exper...

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Mutations in PINK1, which impair its catalytic kinase activity, are causal for autosomal recessive early onset Parkinson's disease (PD). Various studies have indicated that the activation of PINK1 could be a useful strategy in treating neurodegenerative diseases such as PD. Herein, we show that the anthelmintic drug niclosamide and its analogues ar...

N-Myristoyltransferase (NMT) represents a promising drug target within the parasitic protozoa Trpanosoma brucei (T. brucei), the causative agent for human African trypanosomiasis (HAT) or sleeping sickness. We have previously validated T. brucei NMT as a promising druggable target for the treatment of HAT in both stage 1 and 2 of the disease. We re...