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| Autori principali: | , , , , , , , , , |
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| Natura: | Artículo Open Access |
| Pubblicazione: |
Wiley
2025
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| Soggetti: | |
| Accesso online: | https://bpspubs.onlinelibrary.wiley.com/doi/10.1111/bph.70100 |
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Sommario:
- Bispecific nanobody® as a new pharmacological drug for the selective inhibition of Trypsin‐3 Melissa David Anaïs Faihy Corinne Rolland Anissa Edir Astrid Canivet Laetitia Ligat Mireille Sebbag Nathalie Vergnolle Aurélien Olichon Céline Deraison British Journal of Pharmacology AbstractBackground and PurposeProteolytic balance is dysregulated in many diseases, with proteases playing critical roles in pathological pathways. A high level of Trypsin‐3 expression has been implicated as a significant mediator of tumour progression and metastasis, and this protease is associated with poor prognosis for patients in various cancers. Therefore, Trypsin‐3 inhibition has emerged as a promising therapeutic target. However, no physiological or pharmacological inhibitor has yet been described that specifically targets Trypsin‐3. A major challenge in developing a druggable inhibitor for this protease lies in achieving selectivity, as proteases belong to a large enzymatic family with close homologues that share similarities in the three‐dimensional folding of their active conformation.Experimental ApproachAn advanced screening strategy of a large library of synthetic humanised nanobodies was employed to isolate highly selective recombinant antibodies targeting the active conformation of Trypsin‐3. Among five hits, we combined two domains with distinct paratopes and inhibitory mechanisms to generate a macrodrug candidate capable to efficiently block Trypsin‐3 activity.Key ResultsThis bispecific nanobody demonstrated exceptionally high selectivity and affinity for Trypsin‐3 in vitro, as well as a strong ability to inhibit cancer cell migration ex vivo for the PC‐3 cancer cell line.Conclusions and ImplicationsThis study underscores the versatility and potential of synthetic nanobody engineering in the development of highly selective protease inhibitors, paving the way for their consideration as drug candidates for clinical development. 10.1111/bph.70100 http://creativecommons.org/licenses/by-nc-nd/4.0/