Design, synthesis and in vitro evaluation of TMPRSS2 inhibitor analogues as potential anticoronaviral drugs
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Gale, Thomas F. (2024) Design, synthesis and in vitro evaluation of TMPRSS2 inhibitor analogues as potential anticoronaviral drugs. In: "American Chemical Society (ACS) Spring 2024 National Meeting", 17th - 21st March, 2024, New Orleans, USA.
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Abstract
A library of structural derivatives of the guanidinium-based pancreatitis drug camostat mesylate has been synthesised for structure activity relationship studies involving assay of the compounds’ protease inhibition. Camostat has been shown to disruptively bind TMPRSS2, a serine protease required by SARS-CoV2 and related coronaviruses for cell entry and consequent viral infection of the host. Since camostat and the structurally-related guanidinium compound nafamostat are already clinically approved (Japan) for pancreatitis, their established benign safety profile point to repurposing potential for anti-viral therapy; since TMPRSS2 is a mammalian enzyme, any therapeutic activity found among novel structural analogues should be less prone to the drug resistance often observed when viral proteins are targeted.
Despite recent studies on both clinical efficacy and the binding site mechanism of camostat and nafamostat, their structure-bioactivity relationships remain largely unexplored. Here we report an initial synthesis of 20 camostat derivatives which, in conjunction SwissDock in silico molecular binding studies, explore the chemical space along this small molecule scaffold. Camostat molecules comprise four structural units connected by ester and amide bonds, a modular construct that lends itself to the incorporation of structural variety. Novel diversity includes our substitution of camostat’s C-terminal dimethyl amide (-NMe2) ‘tail’ for -NEt2, -N-morpholino, -NHMe and free amide -NH2 functionality. Other camostat derivatives in our library are designed to feature spacer units of altered length or rigidity, or incorporate ‘borrowed’ residues such as the naphthyl unit of nafamostat. We also explore the replacement of camostat’s ester linkages with amide bonds, which despite promising improved water solubility is expected to disrupt a critical acylation of the protease’s catalytic serine via suicide inhibition.
TMPRSS2 inhibition is measured by fluorescence-based assays that utilise Edans-Dabcyl pair mediated fluorescence resonance energy transfer (FRET). A significant range of binding strengths is observed among the derivatives synthesised, some matching the affinity of camostat itself. The results, in conjunction with docking studies, point to worthy synthetic directions for subsequent fine-tuned compound libraries to further optimise protease binding in the overall search for antiviral therapies of increased potency.
| Item Type: | Conference or Conference Paper (Paper) |
|---|---|
| Uncontrolled Keywords: | organic synthesis, SARS-CoV2, antiviral, guanidinium, TMPRSS2 |
| Subjects: | Q Science > Q Science (General) Q Science > QR Microbiology > QR355 Virology R Medicine > RS Pharmacy and materia medica |
| Faculty / School / Research Centre / Research Group: | Faculty of Engineering & Science Faculty of Engineering & Science > School of Science (SCI) |
| Related URLs: | |
| Last Modified: | 30 Mar 2026 16:05 |
| URI: | https://gala.gre.ac.uk/id/eprint/52790 |
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