Developing novel inhibitors of malodour precursor transport in the human axilla.

Deodorants and antiperspirants are among the most important personal care products used every day. As consumers are demanding more from their personal care products, healthcare companies are constantly trying to improve the end-user experience of their products. Unilever, is the market leader with >40% market share, driven by sales of its 3 main brands, Rexona (Sure), Axe (Lynx) and Dove. Current product technology is based mainly on aluminium-containing antiperspirant salts (which also act as antimicrobials), antimicrobial solvents (ethanol, glycols) and fragrance. There is a demand for more targeted interventions, such as interfering directly with the formation of malodour at the molecular level. The production of body odour (BO) occurs during the normal growth of harmless bacterial communities that live on underarm skin, often called skin commensals or the skin microbiota. These bacteria acquire nutrients through the uptake of molecules secreted from the eccrine, sebaceous and apocrine glands in our skin. One of these molecules is a sulphur-conjugated peptide, which is secreted from the apocrine gland and recognised by a transport system designed to move peptides into the bacterial cell. Once inside the cell, the sulphur part of the molecule is split from the peptide and escapes from the bacteria, either through active transport or simple diffusion. Once on the skin, this volatile compound evaporates from the body and enters the air surrounding the individual as body odour. Inhibiting the bacterial transporter responsible for the uptake of the key precursor to thiol-based malodour represents a completely novel approach that holds great potential. For safety reasons, the market potential for a new odour-control technology lies, at least initially, in the non-aerosol segment, which represents about 10% of Unilever's business. The aim of this collaborative LINK award is therefore focused on developing a set of targeted inhibitors against the transport system responsible for the uptake of the odourless sulphur-conjugated peptide, thus eliminating one of the main causes of BO in the underarm. A commercialised peptide transporter inhibitor could potentially create a ~Euro200K per annum business for the new technology manufacturer. Furthermore, given the radical nature of the technology, its launch would be expected to result in significant market growth. This might mean growth of ~10% pa in the first 3 years for Unilever's non-aerosol business, equivalent to ~Euro300 million in cash turnover. There is thus clear potential to benefit the UK economy and to create new jobs for both the chemical supplier and Unilever, which has a global development and manufacturing site in Seacroft near Leeds.

The production of body odour (BO) occurs during the normal growth of harmless bacterial communities that live on underarm skin, often called skin commensals or the skin microbiota. These bacteria acquire nutrients through the uptake of molecules secreted from the eccrine, sebaceous and apocrine glands in our skin. One of these molecules is a sulphur-conjugated peptide, which is secreted from the apocrine gland and recognised by a transport system designed to move peptides into the bacterial cell. Once inside the cell, the odouless precursor is metabolised through the action of cytoplasmic enzymes resulting in the sulphurous thioalcohol part of the molecule being split from the peptide. The thioalcohol moiety then escapes from the bacteria, either through active transport or simple diffusion. Once on the skin, this volatile compound evaporates from the body and enters the air surrounding the individual as body odour. Inhibiting the bacterial transporter responsible for the uptake of the thiol-based malodour precursor represents a completely novel approach that holds great potential for improving deodorant performance. We have previously determined the crystal structure of the peptide transporter responsible for the uptake of the malodour precursor peptide, and identified this as a proton coupled oligopeptide transporter (POT). Using a combined approcach of crystal structure, biochemical and biophysical assays, our goal is to design novel inhibitors that will block transport, with the aim of severely reducing initial uptake of the malodour precursor. Our strategy is to design both small molecule peptide based inhibitors, using a bespoke combinatorial peptide library based on the co-crystal structure, and also develop thermostable single chain antibodies (nanobodies) that block transport from the outside of the cell. A commercialised peptide transporter inhibitor could potentially create a ~Euro 200K per annum business for the new technology manufacturer.

The collaborating company, Unilever Plc, will benefit in a number of ways, through (i) establishing the techniques and skill set to handle and develop assays for bacterial membrane transporters, (ii), understanding the potential of either small molecule or protein-based reagents to block transport function both in vitro and, subject to safety clearance and formulation compatibility, in human deodorant studies, (iii) opening up a new and exciting area of Deodorants research within their R&D division.

In terms of industrial impact on the UK bio-economy, a commercialised peptide transporter inhibitor could potentially create an ~ Euro 200K profit per annum. Given that Unilever's global Deodorants business is primarily based in the UK through its major manufacturing facility & development labs in Leeds, plus the research labs in Merseyside, UK-based ingredient suppliers would be in pole position to exploit this opportunity. Furthermore, given the radical nature of the technology, its launch would be expected to result in significant market growth of ~10% pa globally in the first 3 years for Unilever's non-aerosol business, equivalent to ~Euro 300 million in cash turnover. This would generate significant reinvestment opportunities at Unilever's UK-based factory and R&D labs.

Within the university department of Biochemistry, the major impact will strengthening industrial ties with a major UK Personal Care company, with the clear potential to develop this for CASE awards in the BBSRC funded Oxford Interdisciplinary Bioscience Doctorial Training Partnership (http://www.biodtp.ox.ac.uk/).

More generally this project, and the results we will disseminate in joint publications, will benefit the wider industrial biotechnology sector as they start to develop their own membrane transporter-based projects using structural, biophysical and biochemical based methodology. We will work closely with the university knowledge transfer and intellectual property (IP) office to agree a mutually beneficial contract as part of this project. One of our aims in this project is develop a wider understanding with the general public on how Unilever and the Department of Biochemistry in the University of Oxford are working on this important issue and developing UK biotechnology research. We will make use of the department-funded stall at the annual Oxford Science Festival (https://www.oxscifest.com/) (at a cost of £1500, contributed by the department) held in June each year, to engage with the public on the causes of body odour and how deodorants work. Unilever is committed to public engagement and has set aside up to £10K in in-kind contributions in this grant to our public outreach efforts via the Science Festival. Part of the funding provided by Unilever will be used to set up a feedback survey, which will be used to evaluate the impact of our public presentation on understanding of deodorant based science and this LINK award.