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Start Over Author "Lee Tatham" Journal nature communications
2 results on '"Lee Tatham"'

1. Multivalent bicyclic peptides are an effective antiviral modality that can potently inhibit SARS-CoV-2

Author

Katherine U. Gaynor, Marina Vaysburd, Maximilian A. J. Harman, Anna Albecka, Phillip Jeffrey, Paul Beswick, Guido Papa, Liuhong Chen, Donna Mallery, Brian McGuinness, Katerine Van Rietschoten, Steven Stanway, Paul Brear, Aleksei Lulla, Katarzyna Ciazynska, Veronica T. Chang, Jo Sharp, Megan Neary, Helen Box, Jo Herriott, Edyta Kijak, Lee Tatham, Eleanor G. Bentley, Parul Sharma, Adam Kirby, Ximeng Han, James P. Stewart, Andrew Owen, John A. G. Briggs, Marko Hyvönen, Michael J. Skynner, and Leo C. James

Subjects
Science
Abstract

Abstract COVID-19 has stimulated the rapid development of new antibody and small molecule therapeutics to inhibit SARS-CoV-2 infection. Here we describe a third antiviral modality that combines the drug-like advantages of both. Bicycles are entropically constrained peptides stabilized by a central chemical scaffold into a bi-cyclic structure. Rapid screening of diverse bacteriophage libraries against SARS-CoV-2 Spike yielded unique Bicycle binders across the entire protein. Exploiting Bicycles’ inherent chemical combinability, we converted early micromolar hits into nanomolar viral inhibitors through simple multimerization. We also show how combining Bicycles against different epitopes into a single biparatopic agent allows Spike from diverse variants of concern (VoC) to be targeted (Alpha, Beta, Delta and Omicron). Finally, we demonstrate in both male hACE2-transgenic mice and Syrian golden hamsters that both multimerized and biparatopic Bicycles reduce viraemia and prevent host inflammation. These results introduce Bicycles as a potential antiviral modality to tackle new and rapidly evolving viruses.

Published
2023
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2. Long-acting injectable atovaquone nanomedicines for malaria prophylaxis

Author

Steve P. Rannard, Matthew M. Ippolito, Abhai K. Tripathi, Lee Tatham, Alison C. Savage, Andrew Owen, Elizabeth Nenortas, Godfree Mlambo, Rahul P. Bakshi, and Theresa A. Shapiro

Subjects
0301 basic medicine, Male, Plasmodium berghei, Drug Resistance, General Physics and Astronomy, 02 engineering and technology, Pharmacology, Theranostic Nanomedicine, Mice, lcsh:Science, media_common, Drug Carriers, Multidisciplinary, biology, 021001 nanoscience & nanotechnology, 3. Good health, Chemoprophylaxis, Female, 0210 nano-technology, Atovaquone, medicine.drug, Single administration, Drug, media_common.quotation_subject, Science, Chemoprevention, General Biochemistry, Genetics and Molecular Biology, Article, 03 medical and health sciences, Antimalarials, parasitic diseases, Anopheles, medicine, Animals, Humans, business.industry, Malaria prophylaxis, General Chemistry, medicine.disease, biology.organism_classification, Malaria, Mice, Inbred C57BL, Disease Models, Animal, 030104 developmental biology, Long acting, Nanoparticles, lcsh:Q, business
Abstract

Chemoprophylaxis is currently the best available prevention from malaria, but its efficacy is compromised by non-adherence to medication. Here we develop a long-acting injectable formulation of atovaquone solid drug nanoparticles that confers long-lived prophylaxis against Plasmodium berghei ANKA malaria in C57BL/6 mice. Protection is obtained at plasma concentrations above 200 ng ml-1 and is causal, attributable to drug activity against liver stage parasites. Parasites that appear after subtherapeutic doses remain atovaquone-sensitive. Pharmacokinetic–pharmacodynamic analysis indicates protection can translate to humans at clinically achievable and safe drug concentrations, potentially offering protection for at least 1 month after a single administration. These findings support the use of long-acting injectable formulations as a new approach for malaria prophylaxis in travellers and for malaria control in the field., Long-acting antimalarials could provide improved prophylaxis and treatment options in the field. Here, Bakshi et al. develop a long-acting injectable atovaquone nanomedicine that prevents malaria infection prophylactically for up to 4 weeks in mice with no evidence for generation of resistant parasites.

Published
2018

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