Angus E. McMillan


Last Name

McMillan

First Name

Angus E.

ORCID

0000-0002-8883-1380

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2019 - 201912020 - 20256
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Publications 1 - 7 of 7
  • An integrated console for capsule-based, automated organic synthesis
    Item type: Journal Article
    Jiang, Tuo; Bordi, Samuele; McMillan, Angus E.; et al. (2021)
    Chemical Science
    The current laboratory practices of organic synthesis are labor intensive, impose safety and environmental hazards, and hamper the implementation of artificial intelligence guided drug discovery. Using a combination of reagent design, hardware engineering, and a simple operating system we provide an instrument capable of executing complex organic reactions with prepacked capsules. The machine conducts coupling reactions and delivers the purified products with minimal user involvement. Two desirable reaction classes – the synthesis of saturated N-heterocycles and reductive amination – were implemented, along with multi-step sequences that provide drug-like organic molecules in a fully automated manner. We envision that this system will serve as a console for developers to provide synthetic methods as integrated, user-friendly packages for conducting organic synthesis in a safe and convenient fashion.
  • Stereoretentive Etherification of an α-Aryl-β-amino Alcohol Using a Selective Aziridinium Ring Opening for the Synthesis of AZD7594
    Item type: Journal Article
    McMillan, Angus E.; Steven, Alan; Ashworth, Ian W.; et al. (2019)
    The Journal of Organic Chemistry
  • Automated Chemical Systems and the Synthesis of Human Nerve Growth Factor
    Item type: Doctoral Thesis
    McMillan, Angus E. (2023)
  • A vending machine for drug-like molecules – automated synthesis of virtual screening hits
    Item type: Journal Article
    McMillan, Angus E.; Wu, Wilson W.X.; Nichols, Paula L.; et al. (2022)
    Chemical Science
    As a result of high false positive rates in virtual screening campaigns, prospective hits must be synthesised for validation. When done manually, this is a time consuming and laborious process. Large "on-demand" virtual libraries (>7 x 10(12) members), suitable for preparation using capsule-based automated synthesis and commercial building blocks, were evaluated to determine their structural novelty. One sub-library, constructed from iSnAP capsules, aldehydes and amines, contains unique scaffolds with drug-like physicochemical properties. Virtual screening hits from this iSnAP library were prepared in an automated fashion for evaluation against Aedes aegypti and Phytophthora infestans. In comparison to manual workflows, this approach provided a 10-fold improvement in user efficiency. A streamlined method of relative stereochemical assignment was also devised to augment the rapid synthesis. User efficiency was further improved to 100-fold by downscaling and parallelising capsule-based chemistry on 96-well plates equipped with filter bases. This work demonstrates that automated synthesis consoles can enable the rapid and reliable preparation of attractive virtual screening hits from large virtual libraries.
  • Reagent-Based Scaffold Diversity for DNA-Encoded Library Design: Solid Phase Synthesis of DNA-Tagged sp3-Rich Heterocycles by SnAP Chemistry
    Item type: Journal Article
    Škopić, Mateja Klika; Losch, Florian; McMillan, Angus E.; et al. (2022)
    Organic Letters
    Reactions that require strictly dry conditions are challenging to translate to a DNA-encoded library format. Controlled pore glass solid support-connected DNA oligonucleotide-aldehyde conjugates could be condensed with SnAP reagents and cyclized to various sp3-rich heterocycles. The Boc-group of products provided a handle for product purification, and its facile removal under acidic conditions was tolerated by a chemically stabilized barcode. The reaction provides reagent-based scaffold diversity with functionalities for further library synthesis.
  • Structural basis of ribosomal frameshifting during translation of the SARS-CoV-2 RNA genome
    Item type: Journal Article
    Bhatt, Pramod R.; Scaiola, Alain; Loughran, Gary; et al. (2021)
    Science
    Programmed ribosomal frameshifting is a key event during translation of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA genome that allows synthesis of the viral RNA-dependent RNA polymerase and downstream proteins. Here, we present the cryo–electron microscopy structure of a translating mammalian ribosome primed for frameshifting on the viral RNA. The viral RNA adopts a pseudoknot structure that lodges at the entry to the ribosomal messenger RNA (mRNA) channel to generate tension in the mRNA and promote frameshifting, whereas the nascent viral polyprotein forms distinct interactions with the ribosomal tunnel. Biochemical experiments validate the structural observations and reveal mechanistic and regulatory features that influence frameshifting efficiency. Finally, we compare compounds previously shown to reduce frameshifting with respect to their ability to inhibit SARS-CoV-2 replication, establishing coronavirus frameshifting as a target for antiviral intervention.
  • Chemical Synthesis and Chaperone Peptide Mediated Folding of Human Nerve Growth Factor by Expressed KAHA Ligation
    Item type: Journal Article
    Nötel, Nicolas Y.; McMillan, Angus E.; Pattabiraman, Vijaya R.; et al. (2025)
    ACS Central Science
    Nerve growth factor (NGF) is a powerful neurotrophic protein for treating central nervous system diseases, but its therapeutic utility is limited by severe side effects, including hyperalgesia. These adverse effects arise from pleitropic receptor binding that can, in principle, be modulated by side chain mutations or modification─a task suited for chemical protein synthesis. Despite its small size (13 kDa), the chemical synthesis of NGF has been stymied by exceptional hydrophobicity and the requirement for a 104-residue N-terminal “chaperone peptide” for folding. This study presents a chemical synthesis of NGF using α-ketoacid-hydroxylamine (KAHA) ligations, featuring recombinant production of the chaperone peptide and its chemoselective conversion to a C-terminal α-ketoacid. A novel solubility tag, SOLACE, and ester-forming KAHA ligations enabled assembly of linear proNGF from three synthetic and one recombinant segment. Controlled folding and disulfide-bond formation mediated by the chaperone peptide followed by proteolytic cleavage yielded biologically active synthetic NGF as its noncovalent dimer. The synthetic NGF exhibited comparable activity to recombinant NGF in axon growth assays, establishing a platform for engineering NGF variants with tailored therapeutic properties. This approach provides a versatile framework for the semisynthesis of neurotrophins and related proteins that also require long chaperone peptides for proper folding.
Publications 1 - 7 of 7