2. Academic Validation
  3. An allosteric MALT1 inhibitor is a molecular corrector rescuing function in an immunodeficient patient

An allosteric MALT1 inhibitor is a molecular corrector rescuing function in an immunodeficient patient

  • Nat Chem Biol. 2019 Mar;15(3):304-313. doi: 10.1038/s41589-018-0222-1.
Jean Quancard 1,  Theo Klein 2 3 4 5,  Shan-Yu Fung 6 7,  Martin Renatus 8,  Nicola Hughes 8,  Laura Israël 8,  John J Priatel 6 9,  Sohyeong Kang 6 9,  Michael A Blank 10 11,  Rosa I Viner 10,  Jutta Blank 8,  Achim Schlapbach 8,  Paul Erbel 8,  Jayachandran Kizhakkedathu 4 9,  Frédéric Villard 8,  René Hersperger 8,  Stuart E Turvey 6 7,  Joerg Eder 8,  Frédéric Bornancin 12,  Christopher M Overall 13 14 15
Affiliations

Affiliations

  • 1 Novartis Institutes for BioMedical Research, Novartis Campus, Basel, Switzerland. [email protected].
  • 2 Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, British Columbia, Canada.
  • 3 Department of Oral Biological and Medical Science, Faculty of Dentistry, University of British Columbia, Vancouver, British Columbia, Canada.
  • 4 Center for Blood Research, University of British Columbia, Vancouver, British Columbia, Canada.
  • 5 Department of Clinical Chemistry, Erasmus MC University Medical Center, Rotterdam, Netherlands.
  • 6 Department of Pediatrics, University of British Columbia, Vancouver, British Columbia, Canada.
  • 7 BC Children's Hospital, Vancouver, British Columbia, Canada.
  • 8 Novartis Institutes for BioMedical Research, Novartis Campus, Basel, Switzerland.
  • 9 Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada.
  • 10 Thermo Fisher Scientific, San Jose, CA, USA.
  • 11 AbbVie Biotherapeutics, Inc., Redwood City, CA, USA.
  • 12 Novartis Institutes for BioMedical Research, Novartis Campus, Basel, Switzerland. [email protected].
  • 13 Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, British Columbia, Canada. [email protected].
  • 14 Department of Oral Biological and Medical Science, Faculty of Dentistry, University of British Columbia, Vancouver, British Columbia, Canada. [email protected].
  • 15 Center for Blood Research, University of British Columbia, Vancouver, British Columbia, Canada. [email protected].
PMID: 30692685 DOI: 10.1038/s41589-018-0222-1
Abstract

MALT1 paracaspase is central for lymphocyte antigen-dependent responses including NF-κB activation. We discovered nanomolar, selective allosteric inhibitors of MALT1 that bind by displacing the side chain of Trp580, locking the protease in an inactive conformation. Interestingly, we had previously identified a patient homozygous for a MALT1 Trp580-to-serine mutation who suffered from combined immunodeficiency. We show that the loss of tryptophan weakened interactions between the paracaspase and C-terminal immunoglobulin MALT1 domains resulting in protein instability, reduced protein levels and functions. Upon binding of allosteric inhibitors of increasing potency, we found proportionate increased stabilization of MALT1-W580S to reach that of wild-type MALT1. With restored levels of stable MALT1 protein, the most potent of the allosteric inhibitors rescued NF-κB and JNK signaling in patient lymphocytes. Following compound washout, MALT1 substrate cleavage was partly recovered. Thus, a molecular corrector rescues an Enzyme deficiency by substituting for the mutated residue, inspiring new potential precision therapies to increase mutant Enzyme activity in other deficiencies.

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