Showing papers by "Jennifer R. Hiscock published in 2021"

Advances in applied supramolecular technologies

Abstract: Supramolecular chemistry is a comparatively young field that to date has mainly been focused on building a foundation of fundamental understanding. With much progress in this area, researchers are seeking to apply this knowledge to the development of commercially viable products. In this review we seek to outline historical and recent developments within the field of supramolecular chemistry that have made the transition from laboratory to market, and to bring to light those technologies that we believe have commercial potential. In doing so we hope we may illuminate pathways to market for research currently being conducted.

Amyloid particles facilitate surface-catalyzed cross-seeding by acting as promiscuous nanoparticles.

Abstract: Amyloid seeds are nanometer-sized protein particles that accelerate amyloid assembly as well as propagate and transmit the amyloid protein conformation associated with a wide range of protein misfolding diseases. However, seeded amyloid growth through templated elongation at fibril ends cannot explain the full range of molecular behaviors observed during cross-seeded formation of amyloid by heterologous seeds. Here, we demonstrate that amyloid seeds can accelerate amyloid formation via a surface catalysis mechanism without propagating the specific amyloid conformation associated with the seeds. This type of seeding mechanism is demonstrated through quantitative characterization of the cross-seeded assembly reactions involving two nonhomologous and unrelated proteins: the human Aβ42 peptide and the yeast prion–forming protein Sup35NM. Our results demonstrate experimental approaches to differentiate seeding by templated elongation from nontemplated amyloid seeding and rationalize the molecular mechanism of the cross-seeding phenomenon as a manifestation of the aberrant surface activities presented by amyloid seeds as nanoparticles.

The Evaluation of Ester Functionalised TCF-Based Fluorescent Probes for the Detection of Bacterial Species

Abstract: The ester functionality is commonly seen in the areas of chemical biology and medicinal chemistry for the design of cell‐permeable active molecules Ester‐based pro‐drug/pro‐sensor strategies are employed to mask polar functional groups (i e carboxylic acids) and improve the overall cell permeability of these functional molecules However, their use as reactive units for sensing applications, including bacterial detection, has not been fully explored Herein, we synthesised two TCF‐based fluorescent probes, TCF‐OAc and TCF‐OBu As expected, both TCF‐OAc and TCF‐OBu demonstrated a significant fluorescence (22‐ and 43‐fold, respectively) and colorimetric response (yellow to purple) towards porcine liver esterase (PLE) with a limit of detection of 118 mU/mL and 045 mU/mL, respectively With these results in hand, the ability of these probes to detect planktonic suspensions of gram‐positive Staphylococcus aureus (S aureus) and gram‐negative Pseudomonas aeruginosa (P aeruginosa), and Escherichia coli (E coli) were evaluated Different fluorescence responses for gram‐positive and gram‐negative bacteria were observed between TCF‐OAc and TCF‐OBu After 1 h incubation, TCF‐OAc proved more sensitive towards S aureus, demonstrating a significant fluorescence “turn on” response (16‐fold); whereas, TCF‐OBu was more selective towards P aeruginosa, with a 22‐fold increase in the fluorescence response observed These results demonstrate the influence of the ester chain length on the selectivity for bacterial species

Supramolecular self-associating amphiphiles (SSAs) as nanoscale enhancers of cisplatin anticancer activity

Abstract: Many chemotherapeutic drugs have a narrow therapeutic window due to inefficient tumour cell permeation. Supramolecular self-associating amphiphilic salts (SSAs) are a unique class of small molecules that offer potential as next generation cancer drugs and/or therapeutic enhancement agents. Herein, we demonstrate the cytotoxicity of seven SSAs towards both ovarian and glioblastoma cancer cells. We also utilize the intrinsic fluorescent properties of one of these lead SSAs to provide evidence for this class of compound to both bind to the exterior cancer cell surface and permeate the cell membrane, to become internalized. Furthermore, we demonstrate synergistic effects of two lead SSAs on cisplatin-mediated cytotoxicity of ovarian cancer cells and show that this correlates with increased DNA damage and apoptosis versus either agent alone. This work provides the first evidence that SSAs interact with and permeate cancer cell membranes and enhance the cytotoxic activity of a chemotherapeutic drug in human cancer cells.

The phospholipid membrane compositions of bacterial cells, cancer cell lines and biological samples from cancer patients

Abstract: While cancer now impacts the health and well-being of more of the human population than ever before, the exponential rise in antimicrobial resistant (AMR) bacterial infections means AMR is predicted to become one of the greatest future threats to human health. It is therefore vital that novel therapeutic strategies are developed that can be used in the treatment of both cancer and AMR infections. Whether the target of a therapeutic agent be inside the cell or in the cell membrane, it must either interact with or cross this phospholipid barrier to elicit the desired cellular effect. Here we summarise findings from published research into the phospholipid membrane composition of bacterial and cancer cell lines and biological samples from cancer patients. These data not only highlight key differences in the membrane composition of these biological samples, but also the methods used to elucidate and report the results of this analogous research between the microbial and cancer fields.

Supramolecular self-associating amphiphiles (SSAs) as enhancers of antimicrobial agents towards Escherichia coli (E. coli)

Abstract: Supramolecular self-associating amphiphiles (SSAs) are a class of amphiphilic salt which have demonstrated antimicrobial activity against both Gram-positive and Gram-negative bacteria. Herein, we show that SSAs are also able to increase the efficacy of a range of currently used antimicrobial/therapeutic agents with a range of different chemical structures and modes of antimicrobial action against Gram-negative Escherichia coli, which include: octenidine (an antiseptic); ampicillin (an antibiotic); and cisplatin (a DNA chelating agent). Additionally, we show these effects to be dependent on the order of agent addition. Finally, through completion of a range of 1 : 1 SSA : antimicrobial/therapeutic agent physicochemical studies we gain an understanding as to how the self-association events and resultant SSA aggregate structure are effected by the presence of these secondary molecular species.

An Area‐Specific, International Community‐Led Approach to Understanding and Addressing Equality, Diversity, and Inclusion Issues within Supramolecular Chemistry

Abstract: Diversity, equality, and inclusion (DEI/EDI) are pressing issues in chemistry and the natural sciences. In this Essay we share how an area-specific approach is "calling in" the community so that it can act to address EDI issues, and support those who are marginalised. Women In Supramolecular Chemistry (WISC) is an international network that aims to support equality, diversity, and inclusion within supramolecular chemistry. WISC has taken a field-specific approach using qualitative research methods with scientists to identify the support that is needed and the problems the supramolecular community needs to address. Herein, we present survey data from the community which highlight the barriers that are faced by those who take career breaks for any reason, a common example is maternity leave, and the importance of mentoring to aid progression post-PhD. In conclusion, we set out an interdisciplinary and creative approach to addressing EDI issues within supramolecular chemistry.

Identification of organophosphorus simulants for the development of next-generation detection technologies.

Abstract: Organophosphorus (OP) chemical warfare agents (CWAs) represent an ongoing threat but the understandable widespread prohibition of their use places limitations on the development of technologies to counter the effects of any OP CWA release. Herein, we describe new, accessible methods for the identification of appropriate molecular simulants to mimic the hydrogen bond accepting capacity of the P[double bond, length as m-dash]O moiety, common to every member of this class of CWAs. Using the predictive methodologies developed herein, we have identified OP CWA hydrogen bond acceptor simulants for soman and sarin. It is hoped that the effective use of these physical property specific simulants will aid future countermeasure developments.

Predicting the hydrolytic breakdown rates of organophosphorus chemical warfare agent simulants using association constants derived from hydrogen bonded complex formation events

Abstract: Organophosphorus (OP) chemical warfare agents (CWAs) represent an ongoing global threat, through either purposeful environmental release or the need to dispose of historic stockpiles. This presents a need for the development of novel decontamination technologies. Due to the toxic nature and legal limitations placed on OP CWAs, the use of appropriate OP simulants that mimic the reactivity but not the toxicity of the agents themselves is vital to decontamination studies. Herein, we show that association constants derived from non-specific hydrogen-bonded complexation events may be used as parameters within models to predict simulant reactivity. We also discuss the limitations that should be placed on such data.