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Scientists from Radboudumc have contributed to an Open Science project to discover novel antiviral drugs against SARS-coronavirus-2 (SARS-CoV-2). The COVID Moonshot initiative is a non-profit consortium of over 200 scientists worldwide, dedicated to produce an antiviral drug that is not protected by patents and can be produced quickly and at low cost.
COVID Moonshot started as a bottom-up initiative where scientists were invited via social media to support the project by performing experiments or contributing intellectual input. This led to a virtual consortium working together under the explicit agreement that no intellectual property is claimed and that all generated data are directly made available in the public domain.
The project started with a high throughput crystallographic screen to identify small molecules bound to the main protease (Mpro) of SARS-CoV-2 and to determine the structure of the complex. Information from this screen was used to guide medicinal chemistry to design small molecules expected to bind the active site of the protease. These were synthesized and tested in high throughput in biochemical assays for inhibition of protease activity. The most promising compounds were tested for antiviral activity against the virus itself, which is labor-intensive work that requires a dedicated high-safety laboratory.
Along with several other laboratories across the globe, scientists Gijs Overheul, Pascal Miesen, Finny Varghese, and Ronald van Rij (dept. Medical Microbiology, Research Program Vector-borne Diseases) have contributed to COVID Moonshot by testing drugs candidates for antiviral activity in our biosafety level-3 laboratory. Selected compounds were tested in cell lines as well as in kidney organoids in collaboration with Jitske Jansen and Bart Smeets (dept. Pathology). COVID Moonshot has developed a candidate drug that strongly inhibits the virus at low concentrations in cell culture. This candidate will now enter a further development process towards preclinical studies in collaboration with the Drugs for Neglected Diseases Initiative (DNDi). In addition to identifying a promising new antiviral drug lead, COVID Moonshot has demonstrated the viability of an alternative, Open Science approach to develop antiviral drugs and prepare for future pandemics. The results have recently been published in the journal Science.
Read the study here
Boby ML, Fearon D, Ferla M, Filep M, Koekemoer L, Robinson MC; COVID Moonshot Consortium‡; Chodera JD, Lee AA, London N, von Delft A, von Delft F, Achdout H, Aimon A, Alonzi DS, Arbon R, Aschenbrenner JC, Balcomb BH, Bar-David E, Barr H, Ben-Shmuel A, Bennett J, Bilenko VA, Borden B, Boulet P, Bowman GR, Brewitz L, Brun J, Bvnbs S, Calmiano M, Carbery A, Carney DW, Cattermole E, Chang E, Chernyshenko E, Clyde A, Coffland JE, Cohen G, Cole JC, Contini A, Cox L, Croll TI, Cvitkovic M, De Jonghe S, Dias A, Donckers K, Dotson DL, Douangamath A, Duberstein S, Dudgeon T, Dunnett LE, Eastman P, Erez N, Eyermann CJ, Fairhead M, Fate G, Fedorov O, Fernandes RS, Ferrins L, Foster R, Foster H, Fraisse L, Gabizon R, García-Sastre A, Gawriljuk VO, Gehrtz P, Gileadi C, Giroud C, Glass WG, Glen RC, Glinert I, Godoy AS, Gorichko M, Gorrie-Stone T, Griffen EJ, Haneef A, Hassell Hart S, Heer J, Henry M, Hill M, Horrell S, Huang QYJ, Huliak VD, Hurley MFD, Israely T, Jajack A, Jansen J, Jnoff E, Jochmans D, John T, Kaminow B, Kang L, Kantsadi AL, Kenny PW, Kiappes JL, Kinakh SO, Kovar B, Krojer T, La VNT, Laghnimi-Hahn S, Lefker BA, Levy H, Lithgo RM, Logvinenko IG, Lukacik P, Macdonald HB, MacLean EM, Makower LL, Malla TR, Marples PG, Matviiuk T, McCorkindale W, McGovern BL, Melamed S, Melnykov KP, Michurin O, Miesen P, Mikolajek H, Milne BF, Minh D, Morris A, Morris GM, Morwitzer MJ, Moustakas D, Mowbray CE, Nakamura AM, Neto JB, Neyts J, Nguyen L, Noske GD, Oleinikovas V, Oliva G, Overheul GJ, Owen CD, Pai R, Pan J, Paran N, Payne AM, Perry B, Pingle M, Pinjari J, Politi B, Powell A, Pšenák V, Pulido I, Puni R, Rangel VL, Reddi RN, Rees P, Reid SP, Reid L, Resnick E, Ripka EG, Robinson RP, Rodriguez-Guerra J, Rosales R, Rufa DA, Saar K, Saikatendu KS, Salah E, Schaller D, Scheen J, Schiffer CA, Schofield CJ, Shafeev M, Shaikh A, Shaqra AM, Shi J, Shurrush K, Singh S, Sittner A, Sjö P, Skyner R, Smalley A, Smeets B, Smilova MD, Solmesky LJ, Spencer J, Strain-Damerell C, Swamy V, Tamir H, Taylor JC, Tennant RE, Thompson W, Thompson A, Tomásio S, Tomlinson CWE, Tsurupa IS, Tumber A, Vakonakis I, van Rij RP, Vangeel L, Varghese FS, Vaschetto M, Vitner EB, Voelz V, Volkamer A, Walsh MA, Ward W, Weatherall C, Weiss S, White KM, Wild CF, Witt KD, Wittmann M, Wright N, Yahalom-Ronen Y, Yilmaz NK, Zaidmann D, Zhang I, Zidane H, Zitzmann N, Zvornicanin SN. Open science discovery of potent noncovalent SARS-CoV-2 main protease inhibitors. Science. 2023 Nov 10;382(6671):eabo7201. doi: 10.1126/science.abo7201.
