RT Journal Article SR Electronic T1 Selective pharmaceutical inhibition of PARP14 mitigates allergen-induced IgE and mucus overproduction in a mouse model of pulmonary allergic response JF bioRxiv FD Cold Spring Harbor Laboratory SP 2021.06.05.447208 DO 10.1101/2021.06.05.447208 A1 Alex M. Eddie A1 Kevin Chen A1 Laurie B. Schenkel A1 Kerren K. Swinger A1 Jennifer R. Molina A1 Kaiko Kunii A1 Ariel L. Raybuck A1 Heike Keilhack A1 Mario Niepel A1 R. Stokes Peebles A1 Mark R. Boothby A1 Sung Hoon Cho YR 2021 UL http://biorxiv.org/content/early/2021/06/07/2021.06.05.447208.abstract AB The type 2 cytokines IL-4 and IL-13, which share use of an IL-4 receptor alpha chain and its nuclear induction of the transcription factor STAT6, are crucial in elicitation and maintenance of allergic conditions that include asthma. Prior work has shown a physical and functional association of STAT6 with PARP14, an ADP-ribosyl monotransferase. Moreover, elimination of all PARP14 expression by gene targeting led to altered recall antibody responses and attenuation of ovalbumin-specific allergic lung inflammation with no apparent health issues for mice lacking this protein. However, an unanswered question is whether or not inhibition of the catalytic function has any biological consequence since PARP14 has multiple functional domains apart from the portion that catalyzes ADP-ribosylation. As reported separately, iterative structural analyses and medicinal chemistry fostered the generation of a compound, RBN2759, that is highly selective in its inhibition of PARP14 with negligible impact on other members of the PARP gene family. We show here that administration of this compound to mice previously sensitized to the allergen Alternaria alternata achieved biochemically active levels and altered physiological responses to the antigen. These results show for the first time that in vivo administration of a specific inhibitor of the ADP-ribosyltransferase activity encoded by PARP14 is sufficient to alter biological responses. Specifically, the orally absorbable pharmaceutical compound decreased allergen-induced mucus, blunted the induced increases in circulating IgE, and prevented suppression of IgG2a. We conclude that the catalytic activity can contribute to pathogenesis in allergic processes and propose that other biological endpoints that depend on ADP-ribosylation by PARP14 can be targeted using selective inhibition.Competing Interest StatementAll authors who are or were employees of Ribon Therapeutics, Inc. would benefit financially if the pharmaceutical agent that is central to this report, or derivatives thereof, were to make it to be an approved therapeutic. Thus, K. K., L. S., K. S., J. M., M. N., and H. K. are full-time employees of and hold equity interests in Ribon Therapeutics but were recused from analyses and interpretation of the data and from manuscript preparation; A. M. E., K. C., K. G., A. L. R., R. S. P., and S. H. C. report no potential conflicts of interest; M. R. B. holds equity in Regeneron, Inc., which markets a biologic agent used in treatment of allergic diseases and asthma.ALIallergic lung inflammationIgimmunoglobulinSTATSignal Transducer and Activator of TranscriptionThT helperIL-interleukin-GLTgermline transcriptPARPPoly-(ADP-ribose) PolymeraseARTADP-ribosyltransferaseADPrADP-riboseCD3, 28, 40, etcCluster of Differentiation (molecule #3, 28, 40, etc)ELISAenzyme-linked immunosorbent assayPBSphosphate-buffered salineIC (50)inhibitory concentration achieving 50% effecti.n.intranasalAbantibodyH+Lheavy and light chains (of Ab molecule)WTwild-typeAgantigenMARmono ADPrPARpoly ADPrPASPeriodic Acid SchiffBALbroncho-alveolar lavageTNFtumor necrosis factorLPSlipopolysaccharideMHCmajor histocompatibility complex