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Recent Development of Aminoacyl-Trna Synthetase Inhibitors for Human Diseases: a Future Perspective

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Recent Development of Aminoacyl-Trna Synthetase Inhibitors for Human Diseases: a Future Perspective biomolecules Review Review RecentRecent DevelopmentDevelopment ofof Aminoacyl-tRNAAminoacyl-tRNA Synthetase InhibitorsInhibitors forfor HumanHuman Diseases:Diseases: A Future Future Perspective Perspective Soong-HyunSoong-Hyun Kim Kim, Seri, Seri Bae Bae and and Minsoo Minsoo Song Song * * NewNew Drug Drug Development Development Center Center (NDDC),(NDDC), Daegu-GyeongbukDaegu-Gyeongbuk MedicalMedical Innovation Foundation (DGMIF), 8080 Cheombok-ro Cheombok-ro Dong-gu, Dong-gu, Daegu Daegu 41061, 41061, Korea;Korea; [email protected]@dgmif.re.kr (S.-H.K.); [email protected]@dgmif.re.kr (S.B.) (S.B.) * *Correspondence: Correspondence: [email protected] [email protected] Received: 30 October 2020; Accepted: 27 November 2020; Published: 1 December 2020 Received: 30 October 2020; Accepted: 27 November 2020; Published: 1 December 2020 Abstract: Aminoacyl-tRNA synthetases (ARSs) are essential enzymes that ligate amino acids to Abstract:tRNAs andAminoacyl-tRNA translate the genetic synthetases code during (ARSs) protei are essentialn synthesis. enzymes Their that function ligate aminoin pathogen-derived acids to tRNAs andinfectious translate diseases the genetic has been code well during established, protein synthesis. which has Their led functionto the development in pathogen-derived of small molecule infectious diseasestherapeutics. has been The well applicability established, of whichARS inhibitors has led to for the other development human diseases, of small moleculesuch as fibrosis, therapeutics. has Therecently applicability been explored of ARS in inhibitors the clinical for othersetting. human There diseases, are active such studies as fibrosis, to find has small recently molecule been exploredtherapeutics in the for clinical cancers. setting. Studies There on central are active nervou studiess system to find (CNS) small disorders molecule are therapeutics burgeoning for as cancers. well. StudiesIn this onregard, central we nervous present systema concise (CNS) analysis disorders of the are recent burgeoning development as well. of InARS this inhibitors regard, we based present on asmall concise molecules analysis from of the the recent discovery development research of stage ARS inhibitorsto clinical basedstudies on as small well moleculesas a recent from patent the discoveryanalysis from research the medicinal stage to clinicalchemistry studies point as of wellview. as a recent patent analysis from the medicinal chemistry point of view. Keywords: aminoacyl-tRNA synthetase; small molecule inhibitors; human diseases Keywords: aminoacyl-tRNA synthetase; small molecule inhibitors; human diseases 1. Introduction 1. Introduction Aminoacyl-tRNA synthetases (ARSs) are a family of 20 essential enzymes that ligate amino acids to theirAminoacyl-tRNA corresponding synthetases tRNAs and (ARSs) translate are the a family genetic of code 20 essential during enzymesprotein synthesis that ligate [1]. amino The two- acids tostep their catalytic corresponding reaction tRNAs of ARSs and involves translate the the fo geneticrmation code of duringan enzyme-bound protein synthesis aminoacyl-adenylate [1]. The two-step catalytic(AMP-aa) reaction followed of ARSs by the involves formation the of formation an aminoacylated of an enzyme-bound tRNA (tRNA-aa) aminoacyl-adenylate by transferring the (AMP-aa) amino followedacid to the by thecorresponding formation of tRNA. an aminoacylated This catalytic tRNA reaction (tRNA-aa) of ARSs by transferringplays a pivotal the amino role in acid protein to the correspondingsynthesis, which tRNA. is essential This catalytic for the reaction growth ofand ARSs survival plays of a pivotalall cells role(Figure in protein 1). ARSs synthesis, have long which been is essentialstudied foras therapeutic the growth andtargets survival for pathogen-derived of all cells (Figure infectious1). ARSs have diseases, long beenpredominantly studied as therapeuticbecause of targetsconcerns for that pathogen-derived ARS catalytic site infectious inhibitors diseases, would predominantly block translation because in normal of concerns cells [2–4]. that In ARS this catalyticregard, sitevarious inhibitors seminal would reviews block have translation discussed in normal ARS inhibitors cells [2–4 ].for In the this dev regard,elopment various of antibiotics seminal reviews from havedifferent discussed perspectives ARS inhibitors [5–9]. for the development of antibiotics from different perspectives [5–9]. N O N NH2 tRNA N N N O- HO OH - O O O N NH2 O P O P O P O N O - N -O O N O HO OH N NH2 tRNA ATP N "AMP-aa" N protein "tRNA-aa" O OH synthesis O R + AMP H3N + - PPi H3N CO2 R ARS ARS amino acid ARS (aa) FigureFigure 1. 1.Two-step Two-step catalytic catalytic reactionreaction ofof aminoacyl-tRNAaminoacyl-tRNA synthetases (ARSs). ARSs ARSs use use an an amino amino acid acid (aa),(aa), ATP, ATP, and and tRNA tRNA as as substrates substrates to to produce produce anan aminoacylatedaminoacylated tRNA (tRNA-aa) that that leads leads to to protein protein synthesissynthesis in in the the ribosome. ribosome. Biomolecules 2020, 10, x; doi: FOR PEER REVIEW www.mdpi.com/journal/biomolecules Biomolecules 2020, 10, 1625; doi:10.3390/biom10121625 www.mdpi.com/journal/biomolecules Biomolecules 2020, 10, x FOR PEER REVIEW 2 of 24 Biomolecules 2020 10 However,, a, 1625significant amount of research targeting mammalian ARSs for the treatment2 of of 24 human diseases have recently emerged. For example, febrifugine derivatives, including halofuginone whichHowever, targets prolyl-tRNA a significant synthetase amount of (ProRS), research are targeting under investigation mammalian for ARSs the fortreatment the treatment of cancer, of humanfibrosis, diseases and inflammatory have recently diseases emerged. [10,11]. For example, Additionally, febrifugine threonyl-tRNA derivatives, synthetase including halofuginone(ThrRS) was whichidentified targets as a prolyl-tRNAtarget protein synthetase of antiangiogenic (ProRS), borrelidin are under [12], investigation and a peptide for thefragment treatment derived of cancer, from fibrosis,tryptophanyl-tRNA and inflammatory synthetase diseases (TrpRS) [10,11 was]. Additionally, studied as threonyl-tRNAa possible anti-angiogenic synthetase (ThrRS)agent [13]. was identifiedHowever, asPfizer a target has proteindropped of its antiangiogenic development borrelidin of the TrpRS [12], fragment and a peptide as an fragmentanti-angiogenic derived lead from a tryptophanyl-tRNAwhile ago. Accordingly, synthetase Kwon (TrpRS)et al. [14] was separate studiedly as provided a possible thorough anti-angiogenic reviews agent on the [13 physiology,]. However, Pfizerpathology, has droppedand structural its development aspects of ARSs, of the as TrpRS well fragmentas the development as an anti-angiogenic of ARS inhibitors lead a for while human ago. Accordingly,diseases, including Kwon infectious et al. [14] separatelydiseases, cancer, provided inflammatory thorough reviewsdiseases, on and the central physiology, nervous pathology, system and(CNS) structural disorders. aspects In this of review, ARSs, we as wellfocus as on the the development recent development of ARS of inhibitors ARS inhibitors for human ranging diseases, from includingdiscovery infectiousto clinical diseases,trials from cancer, medicinal inflammatory chemistry diseases, perspectives and centraland provide nervous a related system patent (CNS) disorders.analysis. In this review, we focus on the recent development of ARS inhibitors ranging from discovery to clinical trials from medicinal chemistry perspectives and provide a related patent analysis. 2. Structural Class of ARS Inhibitors 2. Structural Class of ARS Inhibitors 2.1. Benzoxaboroles 2.1. Benzoxaboroles Benzoxaboroles are a class of boron-containing compounds with a broad range of biological activities.Benzoxaboroles A subset of are benzoxaboroles a class of boron-containing have antimicrobial compounds activity withprimarily a broad due range to their of biologicalability to activities.inhibit leucyl-tRNA A subset synthetase of benzoxaboroles (LeuRS) havevia the antimicrobial oxaborole tRNA-trapping activity primarily (OBORT) due to mechanism, their ability towhich inhibit involves leucyl-tRNA the formation synthetase of a (LeuRS)stable tRNA via theLeu− oxaborolebenzoxaborole tRNA-trapping adduct in which (OBORT) the mechanism,boron atom whichinteracts involves with the the 2′ formation- and 3′-oxygen of a stable atoms tRNA of theLeu terminalbenzoxaborole 3′ tRNA adduct adenosi006Ee in which [15]. the boronIn a related atom − interactsstudy, researchers with the 20 -at and Anacor 30-oxygen Pharmaceuticals atoms of the terminal reported 30 tRNA an X-ray adenosi006Ee crystal [structure15]. In a relatedof Thermus study, researchersthermophilus atLeuRS Anacor complexed Pharmaceuticals with tRNA reportedLeu and anthe X-ray benzoxaborole-base crystal structured LeuRS of Thermus inhibitor thermophilus AN2690 LeuRSto form complexed a tRNA–AN2690 with tRNA adductLeu possessingand the benzoxaborole-based tetrahedral spiroborate LeuRS structure inhibitor 1 (Figure AN2690 2) to[16]. form The a tRNA–AN2690tetrahedral spiroborate adduct possessingadduct was tetrahedral stabilized by spiroborate the formation structure of covalent1 (Figure bonds2)[ 16 between]. The tetrahedral the Lewis spiroborateacidic boron adduct atom wasand stabilized the 2′- and by the3′-oxygen formation atoms of covalent of the bonds tRNA’s between 3′-terminal the Lewis adenosine acidic boron as a atomnucleophile and the [17,18] 20- and. The
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