Target Information

Target General Information

Target ID

T59626 (Former ID: TTDC00129)

Target Name

Leukotriene B4 receptor 1 (LTB4R)

Synonyms

P2Y7; P2Y purinoceptor 7; P2RY7; Leukotriene B(4) receptor BLT1; LTB4-R1; LTB4-R 1; LTB4-R; GPR16; G-protein coupled receptor 16; Chemoattractant receptor-like 1; CMKRL1; BLTR; BLT1; BLT

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Gene Name

LTB4R

Target Type

Clinical trial target

[1]

Disease

[+] 3 Target-related Diseases

Human immunodeficiency virus disease [ICD-11: 1C60-1C62]

Pulmonary disease [ICD-11: 1B10-1F85]

Renal cell carcinoma [ICD-11: 2C90]

Function

The activity of this receptor is mediated by G proteins which activate a phosphatidylinositol-calcium second messenger system. May be the cardiac P2Y receptor involved in the regulation of cardiac muscle contraction through modulation of L-type calcium currents. Is a receptor for leukotriene B4, a potent chemoattractant involved in inflammation and immune response. Receptor for extracellular ATP > UTP and ADP.

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BioChemical Class

GPCR rhodopsin

UniProt ID

LT4R1_HUMAN

Sequence

MNTTSSAAPPSLGVEFISLLAIILLSVALAVGLPGNSFVVWSILKRMQKRSVTALMVLNL
ALADLAVLLTAPFFLHFLAQGTWSFGLAGCRLCHYVCGVSMYASVLLITAMSLDRSLAVA
RPFVSQKLRTKAMARRVLAGIWVLSFLLATPVLAYRTVVPWKTNMSLCFPRYPSEGHRAF
HLIFEAVTGFLLPFLAVVASYSDIGRRLQARRFRRSRRTGRLVVLIILTFAAFWLPYHVV
NLAEAGRALAGQAAGLGLVGKRLSLARNVLIALAFLSSSVNPVLYACAGGGLLRSAGVGF
VAKLLEGTGSEASSTRRGGSLGQTARSGPAALEPGPSESLTASSPLKLNELN

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3D Structure

Click to Show 3D Structure of This Target

PDB

Drugs and Modes of Action

Top

Clinical Trial Drug(s)

[+] 3 Clinical Trial Drugs

Amelubant

Drug Info

Phase 2

Pulmonary disease

[2]

LTB4

Drug Info

Phase 2

Human immunodeficiency virus infection

[3]

Biomed 101

Drug Info

Phase 1

Kidney cancer

[4]

Discontinued Drug(s)

[+] 15 Discontinued Drugs

CI-949

Drug Info

Discontinued in Phase 2

Asthma

[7]

CP-195543

Drug Info

Discontinued in Phase 2

Rheumatoid arthritis

[8], [9]

LTB 019

Drug Info

Discontinued in Phase 2

Asthma

[10]

LY293111

Drug Info

Discontinued in Phase 2

Pancreatic cancer

[11], [12]

SB-201993

Drug Info

Discontinued in Phase 2

Psoriasis vulgaris

[13]

CP-105696

Drug Info

Discontinued in Phase 1

Inflammatory bowel disease

[14], [15]

TAK-683

Drug Info

Discontinued in Phase 1

Prostate cancer

[16]

DW-1350

Drug Info

Terminated

Osteoporosis

[20]

LY-210073

Drug Info

Terminated

Asthma

[21]

RG-14893

Drug Info

Terminated

Asthma

[22]

RP-66153

Drug Info

Terminated

Asthma

[23]

RP-66364

Drug Info

Terminated

Inflammation

[24]

RP-69698

Drug Info

Terminated

Inflammation

[25]

SB-209247

Drug Info

Terminated

Psoriasis vulgaris

[26]

SC-53228

Drug Info

Terminated

Asthma

[27]

Mode of Action

[+] 5 Modes of Action

Antagonist

[+] 6 Antagonist drugs

Amelubant

Drug Info

[28], [29]

CP-195543

Drug Info

[34]

LTB 019

Drug Info

[35]

LY293111

Drug Info

[36], [37], [38]

TAK-683

Drug Info

[41]

SB-209247

Drug Info

[48]

Agonist

[+] 1 Agonist drugs

LTB4

Drug Info

[1], [30]

Binder

[+] 1 Binder drugs

Biomed 101

Drug Info

[30], [31], [32]

Modulator

[+] 7 Modulator drugs

CI-949

Drug Info

[33]

DW-1350

Drug Info

[42]

LY-210073

Drug Info

[21]

RG-14893

Drug Info

[44]

RP-66153

Drug Info

[45]

RP-66364

Drug Info

[46]

RP-69698

Drug Info

[47]

Inhibitor

[+] 18 Inhibitor drugs

SB-201993

Drug Info

[39]

CP-105696

Drug Info

[40]

LY-292728

Drug Info

[43]

SB-201146

Drug Info

[39]

SC-51146

Drug Info

[30]

SC-53228

Drug Info

[30]

(3S,4R)-3-Benzyl-7-isopropyl-chroman-4-ol

Drug Info

[40]

(LTB4-(Csa)4)2-Glu-H Conjugate

Drug Info

[49]

DTPA Conjugate

Drug Info

[49]

HYNIC Analogue

Drug Info

[49]

Leucettamidine

Drug Info

[50]

LEUCETTAMINE A

Drug Info

[50]

LY-282210

Drug Info

[43]

SC-50073

Drug Info

[30]

SC-50676

Drug Info

[30]

SC-52073

Drug Info

[30]

SC-52569

Drug Info

[30]

SC-53229

Drug Info

[30]

Cell-based Target Expression Variations

Top

Cell-based Target Expression Variations

Cell-based Target Expression Variations Info

Drug Binding Sites of Target

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Ligand Name: LTB4

Ligand Info

Structure Description

cryo-EM structure of LTB4-bound BLT1 in complex with Gi protein

PDB:7VKT

Method

Electron microscopy

Resolution

2.90 Å

Mutation

Yes

[51]

PDB Sequence

EFISLLAIIL

²⁴

LSVALAVGLP

³⁴

GNSFVVWSIL

⁴⁴

KRMQKRSVTA

⁵⁴

LMVLNLALAD

⁶⁴

LAVLLTAPFF

⁷⁴

LHFLAQGTWS

⁸⁴

FGLAGCRLCH

⁹⁴

YVCGVSMYAS

¹⁰⁴

VWLITAMSLD

¹¹⁴

RSLAVARPFV

¹²⁴

SQKLRTKAMA

¹³⁴

RRVLAGIWVL

¹⁴⁴

SFLLATPVLA

¹⁵⁴

YRTVVPWKTN

¹⁶⁴

MSLCFPRYPS

¹⁷⁴

EGHRAFHLIF

¹⁸⁴

EAVTGFLLPF

¹⁹⁴

LIVVASYSDI

²⁰⁴

GRRLQARRFR

²¹⁴

RSRRTGRLVV

²²⁴

LIILTFAAFW

²³⁴

LPYHVVNLAE

²⁴⁴

AGRALAGQAA

²⁵⁴

GLGLVGKRLS

²⁶⁴

LARNVLIALA

²⁷⁴

FLSSSVNPVL

²⁸⁴

YAFAGGGLLR

²⁹⁴

SAGVGFV

Residue

Distance (Å)

ALA21

4.333

LEU25

4.513

PHE74

3.457

PHE77

3.838

LEU78

3.237

HIS94

4.510

CYS97

4.619

GLY98

3.930

MET101

3.587

TYR102

3.718

VAL105

3.699

Residue

Distance (Å)

VAL152

3.861

GLU185

3.137

GLY189

4.267

TRP234

3.623

TYR237

4.527

HIS238

4.608

ARG267

4.722

ASN268

2.563

ILE271

3.530

PHE275

3.639

Ligand Name: flavin mononucleotide

Ligand Info

Structure Description

Crystal structure of the Human Leukotriene B4 Receptor 1 in Complex with Selective Antagonist MK-D-046

PDB:7K15

Method

X-ray diffraction

Resolution

2.88 Å

Mutation

Yes

[52]

PDB Sequence

GVEFISLLAI

²²

ILLSVALAVG

³²

LPGNSFVVWS

⁴²

ILKRMQKRSV

⁵²

TALMVLNLAL

⁶²

ADLAVLLTAP

⁷²

FFLHFLAQGT

⁸²

WSFGLAGCRL

⁹²

CHYVCGVSMY

¹⁰²

ASVWLITAMS

¹¹²

LDRYLAVARP

¹²²

FVSQKLRTKA

¹³²

MARRVLAGIW

¹⁴²

VLSFLLATPV

¹⁵²

LAYRTVVPWK

¹⁶²

TNMSLCFPRY

¹⁷²

PSEGHRAFHL

¹⁸²

IFEAVTGFLL

¹⁹²

PFLIVVASYS

²⁰²

DIGRRLQARR

²¹²

AKALIVYGST

¹⁰¹¹

TGNTEYTAET

¹⁰²¹

IARELADAGY

¹⁰³¹

EVDSRDAASV

¹⁰⁴¹

EAGGLFEGFD

¹⁰⁵¹

LVLLGCSTWG

¹⁰⁶¹

DDSIELQDDF

¹⁰⁷¹

IPLFDSLEET

¹⁰⁸¹

GAQGRKVACF

¹⁰⁹¹

GCGDSSWEYF

¹¹⁰¹

CGAVDAIEEK

¹¹¹¹

LKNLGAEIVQ

¹¹²¹

DGLRIDGDPR

¹¹³¹

AARDDIVGWA

¹¹⁴¹

HDVRGAIRRF

²¹³

RRSRRTGRLV

²²³

VLIILTFAAF

²³³

WLPYHVVNLA

²⁴³

EAGRALAGQA

²⁵³

AGLGLVGKRL

²⁶³

SLARNVLIAL

²⁷³

AFLSSSVNPV

²⁸³

LYAFAGGGLL

²⁹³

RSAGVGFVAK

³⁰³

LLEGTGAEFL

³¹³

EVLFQ

Residue

Distance (Å)

GLY1009

3.671

SER1010

2.740

THR1011

3.306

THR1012

2.660

GLY1013

3.167

ASN1014

2.763

THR1015

3.222

SER1058

2.561

THR1059

2.786

TRP1060

3.360

GLY1061

2.967

ASP1062

4.577

Residue

Distance (Å)

SER1064

3.160

ILE1065

4.454

GLN1068

4.568

CYS1093

3.505

GLY1094

3.354

ASP1095

3.388

TRP1098

3.385

TYR1100

3.399

PHE1101

3.696

CYS1102

3.121

GLY1103

4.707

GLY1128

4.759

Click to View More Binding Site Information of This Target with Different Ligands

Different Human System Profiles of Target	Top
Human Similarity Proteins of target is determined by comparing the sequence similarity of all human proteins with the target based on BLAST. The similarity proteins for a target are defined as the proteins with E-value < 0.005 and outside the protein families of the target. A target that has fewer human similarity proteins outside its family is commonly regarded to possess a greater capacity to avoid undesired interactions and thus increase the possibility of finding successful drugs (Brief Bioinform, 21: 649-662, 2020). Human Pathway Affiliation of target is determined by the life-essential pathways provided on KEGG database. The target-affiliated pathways were defined based on the following two criteria (a) the pathways of the studied target should be life-essential for both healthy individuals and patients, and (b) the studied target should occupy an upstream position in the pathways and therefore had the ability to regulate biological function. Targets involved in a fewer pathways have greater likelihood to be successfully developed, while those associated with more human pathways increase the chance of undesirable interferences with other human processes (Pharmacol Rev, 58: 259-279, 2006). Human Similarity Proteins Human Pathway Affiliation

Different Human System Profiles of Target

Top

Human Similarity Proteins of target is determined by comparing the sequence similarity of all human proteins with the target based on BLAST. The similarity proteins for a target are defined as the proteins with E-value < 0.005 and outside the protein families of the target.

A target that has fewer human similarity proteins outside its family is commonly regarded to possess a greater capacity to avoid undesired interactions and thus increase the possibility of finding successful drugs (Brief Bioinform, 21: 649-662, 2020).

Human Pathway Affiliation of target is determined by the life-essential pathways provided on KEGG database. The target-affiliated pathways were defined based on the following two criteria (a) the pathways of the studied target should be life-essential for both healthy individuals and patients, and (b) the studied target should occupy an upstream position in the pathways and therefore had the ability to regulate biological function.

Targets involved in a fewer pathways have greater likelihood to be successfully developed, while those associated with more human pathways increase the chance of undesirable interferences with other human processes (Pharmacol Rev, 58: 259-279, 2006).

Human Similarity Proteins

Human Pathway Affiliation

Protein Name	Pfam ID	Percentage of Identity (%)	E value
Olfactory receptor 10A6 (OR10A6)	PF13853	27.273 (57/209)	2.78E-04
Olfactory receptor 1C1 (OR1C1)	PF13853	27.612 (37/134)	3.44E-04
Olfactory receptor 1A1 (OR1A1)	PF13853	24.084 (46/191)	3.00E-03
Olfactory receptor 2T3 (OR2T3)	PF13853	27.820 (37/133)	3.00E-03
Olfactory receptor 2T34 (OR2T34)	PF13853	27.820 (37/133)	4.00E-03
Olfactory receptor 11G2 (OR11G2)	PF13853	21.374 (28/131)	4.00E-03
Olfactory receptor 2AG2 (OR2AG2)	PF13853	28.571 (38/133)	4.00E-03
Olfactory receptor 4F21 (OR4F21)	PF13853	27.966 (33/118)	5.00E-03
Click to Show/Hide the Information of Human Similarity Proteins

KEGG Pathway	Pathway ID	Affiliated Target	Pathway Map
Neuroactive ligand-receptor interaction	hsa04080	Affiliated Target
Class: Environmental Information Processing => Signaling molecules and interaction	Pathway Hierarchy

Chemical Structure based Activity Landscape of Target

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Drug Property Profile of Target

Top

(1) Molecular Weight (mw) based Drug Clustering

(2) Octanol/Water Partition Coefficient (xlogp) based Drug Clustering

(3) Hydrogen Bond Donor Count (hbonddonor) based Drug Clustering

(4) Hydrogen Bond Acceptor Count (hbondacc) based Drug Clustering

(5) Rotatable Bond Count (rotbonds) based Drug Clustering

(6) Topological Polar Surface Area (polararea) based Drug Clustering

"RO5" indicates the cutoff set by lipinski's rule of five; "D123AB" colored in GREEN denotes the no violation of any cutoff in lipinski's rule of five; "D123AB" colored in PURPLE refers to the violation of only one cutoff in lipinski's rule of five; "D123AB" colored in BLACK represents the violation of more than one cutoffs in lipinski's rule of five

Target Poor or Non Binders

Top

Target Poor or Non Binders

Target Poor or Non Binders Info

Target Regulators

Top

Target-interacting Proteins

Target-interacting Proteins Info

Target Profiles in Patients

Top

Target Expression
Profile (TEP)

Target Expression Profile Info

Target Affiliated Biological Pathways

Top

KEGG Pathway

[+] 1 KEGG Pathways

Neuroactive ligand-receptor interaction

NetPath Pathway

[+] 1 NetPath Pathways

IL4 Signaling Pathway

Reactome

[+] 2 Reactome Pathways

Leukotriene receptors

G alpha (q) signalling events

WikiPathways

[+] 6 WikiPathways

Nucleotide GPCRs

GPCRs, Class A Rhodopsin-like

Gastrin-CREB signalling pathway via PKC and MAPK

Spinal Cord Injury

GPCR ligand binding

GPCR downstream signaling

Target-Related Models and Studies

Top

Target Validation

Target Validation Info

References

Top

REF 1

LTB4 promotes insulin resistance in obese mice by acting on macrophages, hepatocytes and myocytes. Nat Med. 2015 Mar;21(3):239-47.

REF 2

ClinicalTrials.gov (NCT02249338) Effect of BIIL 284 BS on Patients With Chronic Obstructive Pulmonary Disease (COPD) in Boehringer Ingelheim.

REF 3

ClinicalTrials.gov (NCT00251537) A Pilot Study of LTB4 in HIV-1 Infected Adults in LTB4 Sweden AB.

REF 4

ClinicalTrials.gov (NCT00004890)Biomed 101 and Interleukin-2 in Treating Patients With Kidney Cancer in National Cancer Institute (NCI).

REF 5

URL: http://www.guidetopharmacology.org Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 3415).

REF 6

Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800002326)

REF 7

Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800000104)

REF 8

REF 9

ClinicalTrials.gov (NCT00424294) A Study Of CP-195543 And Celecoxib Dual Therapy In Subjects With Rheumatoid Arthritis. U.S. National Institutes of Health.

REF 10

Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800015581)

REF 11

REF 12

Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800003262)

REF 13

Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800003335)

REF 14

REF 15

Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800005644)

REF 16

Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800028256)

REF 17

Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800005401)

REF 18

REF 19

Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800001833)

REF 20

Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800026567)

REF 21

Design, synthesis, and pharmacological evaluation of potent xanthone dicarboxylic acid leukotriene B4 receptor antagonists. J Med Chem. 1993 Jun 11;36(12):1726-34.

REF 22

Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800001715)

REF 23

Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800003980)

REF 24

Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800003795)

REF 25

Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800003683)

REF 26

Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800006734)

REF 27

Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800006478)

REF 28

Leukotriene receptor antagonists in children with cystic fibrosis lung disease : anti-inflammatory and clinical effects. Paediatr Drugs. 2005;7(6):353-63.

REF 29

Gateways to clinical trials. Methods Find Exp Clin Pharmacol. 2005 Jan-Feb;27(1):49-77.

REF 30

Synthesis and pharmacological activity of SC-53228, a leukotriene B4 receptor antagonist with high intrinsic potency and selectivity, Bioorg. Med. Chem. Lett. 4(6):811-816 (1994).

REF 31

Biomed 101, a leukotriene B4 inhibitor, may decrease IL-2 toxicity. 2003 ASCO Annual Meeting. 2003.

REF 32

Multiple actions of the leukotriene B4 receptor antagonist SC-41930. J Pharmacol Exp Ther. 1992 Jan;260(1):187-91.

REF 33

Inhibition of histamine, leukotriene C4/D4, and thromboxane B2 release from human leukocytes and human chopped lung mast cells by the allergic mediator release inhibitor, CI-949. J Allergy Clin Immunol. 1990 Dec;86(6 Pt 1):902-8.

REF 34

The synthesis of CP-195543, an LTB4 antagonist for the treatment of inflammatory diseases. Curr Opin Drug Discov Devel. 1999 Nov;2(6):550-6.

REF 35

Effect of the oral leukotriene B4 receptor antagonist LTB019 on inflammatory sputum markers in patients with chronic obstructive pulmonary disease. Pulm Pharmacol Ther. 2008;21(2):409-17.

REF 36

The Role of PPARgamma Receptors and Leukotriene B(4) Receptors in Mediating the Effects of LY293111 in Pancreatic Cancer. PPAR Res. 2008;2008:827096.

REF 37

A phase I study of oral LY293111 given daily in combination with irinotecan in patients with solid tumours. Invest New Drugs. 2007 Jun;25(3):217-25.

REF 38

Leukotriene B4 receptor inhibitor LY293111 induces cell cycle arrest and apoptosis in human anaplastic large-cell lymphoma cells via JNK phosphorylation. Leukemia. 2005 Nov;19(11):1977-84.

REF 39

(E)-3-[6-[[(2,6-dichlorophenyl)thio]methyl]-3-(2-phenylethoxy)-2- pyridinyl]-2-propenoic acid: a high-affinity leukotriene B4 receptor antagonist w... J Med Chem. 1996 Sep 13;39(19):3837-41.

REF 40

3-Substituted-4-hydroxy-7-chromanylacetic acid derivatives as antagonists of the leukotriene B4 (LTB4) receptor, Bioorg. Med. Chem. Lett. 7(17):2307-2312 (1997).

REF 41

A second leukotriene B(4) receptor, BLT2. A new therapeutic target in inflammation and immunological disorders. J Exp Med. 2000 Aug 7;192(3):421-32.

REF 42

Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800026850)

REF 43

Biphenylyl-substituted xanthones: highly potent leukotriene B4 receptor antagonists. J Med Chem. 1993 Nov 26;36(24):3982-4.

REF 44

Structure-activity relationships study of two series of leukotriene B4 antagonists: novel indolyl and naphthyl compounds substituted with a 2-[methyl(2-phenethyl)amino]-2-oxoethyl side chain. J Med Chem. 1996 Sep 13;39(19):3756-68.

REF 45

Omega-[(omega-arylalkyl)thienyl]alkanoic acids: from specific LTA4 hydrolase inhibitors to LTB4 receptor antagonists. J Med Chem. 1992 Aug 21;35(17):3170-9.

REF 46

WO patent application no. 1997,0297,75, Compositions comprising a cyclooxygenase-2 inhibitor and a leukotriene b4 receptor antagonist.

REF 47

omega-[(4,6-Diphenyl-2-pyridyl)oxy]alkanoic acid derivatives: a new family of potent and orally active LTB4 antagonists. J Med Chem. 1992 Nov 13;35(23):4315-24.

REF 48

Formation and protein binding of the acyl glucuronide of a leukotriene B4 antagonist (SB-209247): relation to species differences in hepatotoxicity. Drug Metab Dispos. 2005 Feb;33(2):271-81.

REF 49

Synthesis of leukotriene B4 antagonists labeled with In-111 or Tc-99m to image infectious and inflammatory foci. J Med Chem. 2005 Oct 6;48(20):6442-53.

REF 50

New leukotriene B4 receptor antagonist: leucettamine A and related imidazole alkaloids from the marine sponge Leucetta microraphis. J Nat Prod. 1993 Jan;56(1):116-21.

REF 51

Structural basis of leukotriene B4 receptor 1 activation. Nat Commun. 2022 Mar 3;13(1):1156.

REF 52

Structural insights on ligand recognition at the human leukotriene B4 receptor 1. Nat Commun. 2021 May 20;12(1):2971.

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