Ji.i.rgen Drew and tefan Ry er
~ e term "g n mi ·ci n e " land f r the totality falls icntili , llempt t 1 \..,, un er' tand the tructure nd fun ti n f th human g n me an fall Lher genomes. The scientific mission of genomic cience is not defined b the analy is f inglc gene carrying pecific ·tru tural or fun Lion I haractcr ; r ther, gen mi s ·ien es attempts t under tan rhe way in which a p:irLi ular el f gene (3,0 0 in bacte• ria, ,000 in yeast, approximately 100,000 in humans) contributes to th hape, the func- li n, and the development f whole organism fr m c n eption t death.
The pmemial of genomic cien sf r medicine i fourfi ]d: In Lhe fir l place, the knowl• edg of the gene allcrali n - that cau e di ·ea. will lead t a new unders and in• of "di ea e disp "iti n." Thi knowledge \ ill inc itably lead to n vcl or greatly improved diagnostic method . econd1 the abilit c:onveyed by gi.:nomic iences lo diagno e di e, e di posi- l'i n \ i.11 open Lh d r or preventive meJic. I trategic . Thfrd, gen mi will lead lo th identification o new drug target~. These new drug targets will alJaw the ·ynthe ·is of ·mall mol cu]e with n vel me h ni ms of action. Fin lly, we will be able l relate certain geno• L)1 e. t the acti n f drug . hi · \ ill all w the cla i 1c.1tion r patient · int group · potential r spondcrs and non responder to already existing and nc, mectications.
hile all the e area · are imp rtant L the pharmaceu'li al indu try, the id n1if 1cation of novel drug targets is of particular interest to drug di cover}' 1.::fforts. We bav c ti mated the number f I Len Lia I drug target · · ·pe ted t be tleri ed from gen mi . l e in the r nge 3, 00 to I 0,000'. This estimate i ba ed n the a umpli n that Lher arc ab ut I 00 no. ological entitie that represent ma· r multifacl rial diseas ; Lhal on a erage, c.1ch r the: di ca e i generat •d by contribu i n fr m l gene·; and that ea h r these "
I. Oft'w~ ,. 19 b G,'ll<1mk Klcn,c:s~nd rhc medtdn 11f1omomi l. Gootln-u,n wnJ o1lm•n'• rl,r f'lrnrm11ru/oyiro/ 8nm of TT1tn1pt,.,lo.. 9th · ll-u,. ·I hll. ~ York.
Tllrgc:n Oitw< u pr.,..Jdrnt ,if glnhJI r...arcit and 1efan II\...,, i ,:hlcf af i11tcrm1tinm,I ""4:'Jrdi ,ti ~' Hoffmonn·Li ltoch• ltd , I ~,. 'wllnrl~nd. Th ~uthu,.., w ih ltl 1.b,u1I. Y,onnc h;itcr lnr =•<'.'Wing the lllble.
- nature biotec ru
Target Number ~ c...,ynaptic and Neuroeffector Junctional Sites and Central Nervous System ty pe o f ta rgets .. . C ...... 1 5-hydroxytryptamine selective neurotransmitter/serotonin transporter ...... E ...... 1 Acetylcholinesterase ...... •. J ...... R ...... 5 Adrenergic receptors, a., o:2, p., (32, f3J .... •.....•·• ...... • .• ...... E ...... 1 (3-amyloid ...... : ...... • ...... R : . .. ..1 Benzodiazepine receptor ...... • , . . , . • ...... , ...... •• • • ••• • 1 • • • • / •• .' • • ~ - ••• •• • ••••••• •• ••••• • ••• \ • • ••• •• •••• .*.E ...... Butyrylcholinesterase ...... 1 •• 1 ...... -~· ...... c ...... 1 Ca ' channel ...... • . . . . . '/':. • ...... • • ...... • • • .•.•E ...... 1 Catechol-0-methyltransferase . . • . •li: .. • ,;. • • • • • . . • • . .•.....••...... • •. • • • . . •. •...... •••• •• •••••••••• • • •••• • • •••• • • •• • • ••• • R ...... 2 Cholecystokinin ( CCKA> CCK8) • • , •• •• ; •• •••••• , • • • •••• ...... E ...... l Choline acetyltransferase ...... • ...... • . • ...... •. ... R ...... 5 Dopamine 1-5, D1-5 ...... ~. ·l ' ...... R . ... .14 GABAA receptor 60: variants, 3(3, 26, 3y'o/.iilnt •...... •• ..E ...... 1 GABA transaminase ...... • ...... E ...... 1 Glutamic acid decarboxylase ...... ·1· ...... - ...... ~ ~:::::: : : : : g;~:~:~rt:c::,i::;t~:epr~~~~~~r_s'. ~:~· . . ~ ~~ . ·• . . . . -.7: ~~~ ~ ~~A: ~'. ~~~~.~ ~~.: :: :: .. :~~ R ...... 3 H., H , H • • • • • • • • • • • • • ••• .. .. me, 3 .. .. Histam 2 1,.1 ..; ...... ,. ... .•...... , .C ...... 1 Ion channel associated with GABA!)~ pfQr. . · ~· ·( ·/· ...... •••• .E . .... •• I Ka inic acid, agonist, a subunit of the Cai+ Qll,m ~-'dependent protein kinase H · ~ . .. •...... U • .... . 1 Li+ (wtl
HistaminereceptorsH1,H2,H3 •••••••••••••••••••••••••••••••••••••••••••••••••••••••••••• ••• •R ...... 3 Inorganic acid transport (inhibitor) ...... U ...... l Intercellular adhesion molecule 1 ...... •..R ...... 1 Interleukin 1 receptor ...... R ...... 1 Kallikrein, aprotinin, C-esterase, ex2 macroglobulin ...... E , .• ,; ... .4 Kinin ...... E .,f .. ...1 L-type calcium channel ...... C ...... 1 Leukocyte integrins ...... R ...... l Leukotriene A hydrolase ...... E ...... 1
Leukotriene B4 receptor ...... R ...... 1 Leukotriene C4receptor ...... R ...... 1 Leukotriene C synthase ...... E ...... 1
Leukotriene DJ E4 receptor ...... R ...... 1 Lipocortin (protein) that inhibits phospholipase A2 ••• ••• •• •••••• •• ••••••• •• ••• ••••••• •• •• • ••••••• F&H .... I Lipoxygenases: 12-lipoxygenase (platelets), 5-lipoxygenase (leukocytes) ...... E ...... 2 N-acyl hydrolase ...... E ...... I Phosphodiesterase {type IV, cyclic nucleotide phosphodiesterase) ...... E ...... 1 Phospholipase A2, C ...... E ...... 2 Platelet-activating factor receptor (antagonist) ...... R ...... 1 Prostacyclin synthase ...... E ...... l · Prostaglandin 15-0H dehydrogenase (PGDH) ...... E ...... 1 Prostaglandin D - DP receptor ...... R ...... I
Prostaglandin E., E2, E3 - EP receptor ...... R ...... 3 Prostaglandin F - FP receptor ...... R ...... 1 , Prostaglandin Ii-IP receptor ...... R ...... 1 Renal tubular rebsorption of uric acid ...... U ...... l
Serotonin (5-HT3) •••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••R ...... 1 Spindle formation inhibitor during meiosis in neutrophils ...... E ...... 1
Thromboxane A2 TP receptor, platelet and non-platelet ...... R ...... 2 Thromboxane synthase ...... E ...... l Twnor necrosis factor receptor ...... R ...... I Vascular cellular adl1esioo molecule 1 ...... R ...... I Subtotal ( I C, 19 E, 1 f &H, 26 R, 2 U) ...... 49
'}\enal and Cardiovascular Functions 3-hydroxy-3-methylglutaryl coenzyme A ...... E ...... 1 ex-adrenergic receptor ...... R ...... 1 ex-subunit of Na+/K+ ATPase (3 isoforms) ...... E ...... 3 Angiotensin-converting enzyme (ACE) ...... E ...... 1 Angiotensin II forn1ation ...... E ...... l Angiotensin II receptor (antagonist) ...... R ...... 1 Antiplatelet/antithrombotic agent ...... U ...... 1 Arginine vasopressin ...... R ...... 1 Angiotensin receptors, AT1 , AT 2 •••••••••• ••• • • •••••••••••• • •••••• • ••• • ••••••• •• ••• •••• •••••• •• • R ...... 2 ATP-sensitive K1· channel ...... C ...... 1 P-adrenergi.c rec.eptors, p1 •••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••R ...... l Carbonic anhydrase, type l V, 11 ...... E ...... 2 Expression of hepatic LDL receptor (assumed mechanism of action) ...... U ...... I G-protein coupled adenosine receptor ...... R ...... I Ganglionic adrenergic neurons/norepinephrine transporter ...... C ...... I Guanylate cyclase (nitroprusside) ...... E ...... I Guanylyl cyclase (NO) ...... E ...... l Hepatic sulfotransferase as a catalyst ...... E ...... 1 Hyclralizine causes direct relaxation of arteriolar smooth muscle (wlknown molecular mechanism) ...... U ...... 1 L-a romatic amino acid decarboxylase ...... E ...... 1 L-type voltage sensitive Ca2+ channels ...... C ...... 1 Lipoprotein lipase ...... E ...... I Mineralocorticoid receptor (MR) ...... NR .....I Na+ channel ex, p, y ...... C ...... 3 Na+ conductance channel ...... C ...... 1 Na+/CI- sy1uporter ...... C ...... 1 Na+/K+/2Cl- symporter ...... C ...... 1 Neutral n ooe t" ase (NEP), em.vme that deirrades atril oatriuretic peptide (ANP) ...... E ...... I .rrouu<.:al n.:!t..t!_p lUl (H.lt:\..lllll, c:.tpu r \.- .1 ptUUU\..UVJJ \ L_L.l' L 11,.;\..\;.}'lV l UJUI.-PVJl\..l\,.UI.. l Ul,..\.,UU .u ..i.> .a.UJ • • • • • • • • • • • • • • • .... , •• ••• .. a.. Secretion of vasopressin K receptor ...... R ...... I Type I cyclic nucleotide phosphodiesterase ...... E ...... 1 Type Ill cyclic AMP phosphodiesterase ...... •...... E ...... 1 Type V cyclic nucleotide phosphodiesterase ...... E ...... 1
Vasopressin receptors V 10, V 1b, V 2, ....•. •• .•• •••• ••..• .. . . •••• • •. •••••••.....••••••• • • •• •••. . .. • R ...... 3 Water channels in the collecting ducts (aquaporin CD) ...... C , . . ...1 Subtotal (11 C, 17 E, l N R, 15 R, 3 U ) ...... 47
'3astrointestinal Functions
5-HT3 antagonist ...... R ...... 1
5-HT4 receptor ...... R ...... 1 DI dopaminergic receptor ...... R ...... 1 H~·, K+ ATPasc, proton pun1p ...... , ...... C ...... 1
H 1 histamine receptor ...... R ...... 1 H 2 histamine receptor ...... R ...... 1 HCL secretion by gastric cells (antacid) ...... U ...... 1 µ and oreceptor in gastrointestinal tract ...... R ...... 2 Ml receptor, muscarinic cholinergic ...... R ...... 1 Mucosal barrit:r Lo H CI ...... U ...... I Mucus secretion/mucus layer that covers the gastric and duodenal mucosa ...... U ...... 1 Pancrelipase ...... E ...... 1
Prostaglandin E2 (PGE2) ••••• •• •••• •• •••••• •••• • ••••• •••• ••• ••• •••• • •••••••••••••••••••••.•••••R ...... 1 Prostaglandin 12 (PGii) ...... R ...... 1 Subtotal (1 C, l E, 10 R, 3U) .. : ...... 1 5
Uterine Motility 13-adrenergic receptor ...... R ...... 1 Ca2+ channel ...... C ...... 1 Cycloo>..rygenase ...... E ...... 1 Motor activity of tl1e uterus (alkaloids) ...... R ...... I Oxytocin ...... F&H ... . l
Prostaglandin E2 receptor ...... R ...... 1 Prostaglandin Fu, receptor ...... R ...... 1 Prostaglandin synthetase ...... E ...... 1 Subtotal ( 1 C, 2 E, l F&I I, 4 R) ...... 8
J3acterial In fections 23S rRNA of the SOS ribosomal unit ...... E ...... 1 30S rRNA from SOS ribosomal unit ...... E ...... 1 SOS ribosomal unit binding site ...... E ...... 1 Aminoacyl tRNA site on 30S ribosomal unit (tetracycline) ...... E ...... 1 (3-lactamase ...... E ...... 1 (3-subunit of DNA-dt:pt:ndt:nl RNA polymernse ...... E ...... 1 o-alanyl o-alanine synthetase ...... E ...... 1 Dihydropteroate syuthetase ...... E ...... 1 DNA gyrase, subunit a ...... E ...... 1 DNA gyrase, subunit a ...... E ...... 1 L-alanyl racemase ...... E .•.. . • . 1 Microbial dihydrofolate reductase ...... E ...... 1 Mycobacterial RNA polymerase ...... E ...... 1 Mycolic acid biosynthesis (unknown molecular target) ...... E ...... 1 Mycolic acid integration into cell wall (ethambutol), unknown molecular target ...... U ...... 1 PBP 2a, 2b ...... U ...... 2 PBP 3, 4, 5, 6, 7 ...... U ...... 5 Penicillin-binding protein la (PBP la, l b), transpeptidase ...... E ...... 2 Penicilloyl enzyme ...... E ...... l Peptidyl site of the SOS ribosomal unit ...... E ...... 1 Reverse transcriptase ...... E ...... 1 Ribosomal protein from SOS ribosomal unit (streptomycin) ...... E ...... 3 Transpeptidase ...... E ...... 1 Unknown (streptomycin, other than known targets of streptomycin) ...... U ...... 1 Subtotal (23 l;., 9 U) ...... 32 Fungal Infections Cytochrome P450-dependent sterol 14 a-demethylase ...... E ...... 1 Membrane components to increase permeability ...... U ...... l Micro tubular protein ...... E ...... 1 Thymidyla te synthetase ...... E ...... 1 U ridine monophosphatc pyrnphosphorylase ...... E ...••.. I Subtotal ( 4 l E, U) ...... 5
C: Channel; 0: DNA; E: Enzyme; f&H: Factors and Hormones; NR: Nuclear Receptor; R: Receptor; U: Unknown.
Source: Goodman & Gilman's The Pl,armacological Basis ofTl1erape11tics, Ninth Edition, 1996, McGraw-Hill, New York. Sections arc ordered according to chapters in Goodman & Gilman.
FOR INFORMATION CONCERNING REPRINTS OF THIS POSTER CALL ERIC GORDON (212) 726-9261. g argeta
Target Number \) iral Infections type o f targets Helicase ...... E ...... 1 HSY thy1nidine kinase ...... E ...... 1
Influenza A virus M2 protein ...... E ...... 1 Tnosine 5' phosphatedehydrogenase ...... E ...... 1 Integrase ...... E • ...... 1 Neuramidase ...... : ...... E ...... 1 Primase ...... E ...... 1 Reverse transcriptase ...... • ... ~ ...... , ...... • •,...... E ...... 1 Thymidylate syntl'ietase ...... : .. : .. ·~· ...... E ...... I Viral DNA polymerase ... :~ ...... E ...... 1 Subtotal ...... •. . . . I 0
...... E ...... 1 ...... E ...... 1 ...... E ...... I ...... NR .....1 ...... NR .....1 ~=~~ ~ ~ ····· ···· ·········· ···················u ...... 1 ...... D ...... l •....•...... •...... E ...... 1
Jmmunomodulation . ¥ Calcineurin ...... r··· .. . '....•...... F&H ....1 CD3 glycoprotein on T lymphocytes ...... : ...... ~ ...... R ...... 1 Corticosteroid-nuclear receptor ...... NR ..... 1 Cyclophilin, cyclosporiil binding protein ...... F&H .... 1 Dihydrofolate reductase ...... E ...... 1 DNA alk--ylation ...... DNA ... 1 FKBP, tacrolimus binding protein, FK506 bindingprotein ...... F&H .... 1 Granulocyte colony-stimulating factor ...... -...... F&H .... 1 Granulocyte-macrophage colony-stimulating factor ...... F&H ....1 Inosine monophosphate dehydrogenase (de novo synthesis of purines) ...... E ...... 1 lntercalations into DNA backbone ...... DNA ... 1 Interferon ex .••••••••••••••••••••••••••••••••••••••••••.••••.•••••••••••••••••••••••••••••••F&H .. . . 1 Interferon a. receptor ...... R ...... 1 Interleukin-2 receptor (IL-2R) ...... R ...... I Rh O .•...... ••.....· ...... •.....••.• .•...... •...... R ...... I Thymic lymphocyte antibodies ...... U ...... I Subtotal (2 D, 2 E, 6 F&II, J NR, 4 R, I U) ...... 1 6
J3tood and Blood-Forming Organs a 2 antiplasmin ...... F&H .... 1 Anticoagulant protein C ...... F&H .... 1 Anticoagulant protein S ...... F&H . ...1 Coagulation factor JI, VII, IX, X ...... : ...... F&H .. . .4 Cyclic nucleotide phosphodiesterase ...... E ...... 1 Cyclooxygenase (aspirin) ...... E ...... 1 Erythropoietin ...... F&H . ... 1 Factor VITI ...... F&H .... 1 Folic acid ...... R ...... 1 Granulocyte colony-stimulating factor ...... F&H ....1 Granulocyte-macrophage colony-stimulating factor ...... F&H ....1 Endo-J3-o-glucuronidase (heparin) ...... R ...... 1 HPnarin anta(Joni~t .. . F& . . 1 Riboflavin ...... R ...... I Stem cell factor, c-kit ligand ...... F &H ... . 1 Thro1nbopoietin ...... F&H ... . 1 Tissue plasminogen activator ...... F &H .... I
Vitamin 8 12 ••••••• • ••••• ••• •••••• • ••••••• •• ••••• • ••• •••••••••••• ••• •••••••••••• •••• • •••••• • R ...... 1 Vitamin K antagonist ...... R ...... I Subtotal (2 E. 29 F&l-1 , 7 R) ...... 38 fiormones and Hormone Antagonists 3P bydroxysteroid dehydrogenase ...... E ...... 1 a-amylase ...... E ...... I a-glucosidase ...... E ...... 1 ACTH receptor ...... R ...... 1 Adrenocorticotropic hormone (ACTH) ...... F&H .. . . 1 Androgen receptor (te,stosterone receptor) ...... R ...... 1 Aromatase ...... E ...... 1 ATP sensitive K + channels ...... C ...... 1 Calcitonin ...... F&H .... 1 Cell surface receptors for sulfonylureas on pancreatic f\ cells ...... R ...... 1 Cytochrome P450 11~ (llP hydroxylase) ...... E ...... 1 Cytochrome P450 17a Cl7-20 lyase ...... : ...... E ...... 1 Cytochrome P450 aldo, aldosterone synthase ...... E ...... 1 Cytochrome P450 side chain cleavage (sec) enzyme ...... E ...... 1 Dopan1inergic agonist ...... : ...... R ...... 1 Estrogen receptor ...... R ...... 1 Follicle-stimulating hormone (FSH) ...... F&H .... 1 FSH receptor ...... R ...... I GHRH receptor ...... R ...... 1 Glucagon receptor ...... _...... R ...... 1 Glucoarnylase ...... E ...... 1 Glucocorticoid receptor ( GR) ...... R ...... 1 GnRH receptor ...... R ...... 1 Gonadotropin releasjng hormone (Gn RH) ...... F&H .. . . l Growth hormone receptor ...... R ...... I Growth hormone-releasing hormone (GHRH) ...... F&H .. . . 1 IGF-1 receptor, IGF-2 receptor ...... R ...... 2 Insulin ...... F&H . ... 1 Insulin-like growth factor (IGF-l , IGF-2) ...... F&H ....2 Insulin receptor, a and p subunits ...... R ...... 2 Insulin transporter ...... C ..•... l lodothyronine-5 '-deiodinase, type 1, type 2 ...... E ...... 2 LH/choriogonadotropin (CG) receptor ...... R ...... 1 Luteinizing hormone (LH) ...... F&H .... 1 Mineralocorticoid receptor ...... R ...... 1 Parathyroid hormone (PTH ) ...... F&H .. . . 1 Peroxidase ...... E ...... 1 Progesterone receptor (RU486 binding receptor) ...... R ...... 1 Prolactin ...... F&H ....1 Prolactin receptor ...... R ...... 1 Somatostatin ...... F&H .. . . 1 Somatostatin receptors, several ...... R ...... 2 Steroid 5 a reductase 1,2 ...... E ...... 2 Sucrase ...... E ...... 1 Thyroid-stimulating. hormone (TSH) receptor, TRa 1, 2, TRP 1, 2 ...... R ...... 4 Vitamin D nuclear receptor ...... NR .. .. . 1 Subtotnl (2 C, 14 E, 1 I F&H , 3 .N'.R, 25 R) ...... 55
Che Vitainins Ascorbic acid ...... U ...... 1 Carnitine ...... R ...... 1 Mutated bioti_n-dependent enzymes ...... E ...... 1 Nicotinic acid ...... R ...... 1 Pyridoxine ...... R ...... 1 Retinoic acid a receptor ...... NR ..... 1 Thiamine ...... R ...... l vna1nu1 A •. •••• .•.• •. .•.••...... •. ...•..•. .• ..• •• ••• • .•• • ..•• . • ....•••.••.•....•NK ... .. 1 Vitamin E ...... U ...... 1 Vitamin K ...... U ...... 1 Subtotal ( l E, 2 NR, 4-R, 3 U) ...... 10
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