IM
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`90l£5
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`
`Roxane Labs., Inc.
`Exhibit 1012
`Page 001
`
`

`
`/\,\\Elli CAN
`
`l\SSOCJ,\TION FOil Till·.
`
`t\J>\'1\NCl-.Ml·:Nr OF
`
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`
`----
`
`'
`
`IS~N 0036-8075
`18 JANUA!l Y 1991
`VOLU,\1E 251
`NnM111·1l ,~991
`
`247 This \Vcck in Scic11ct>
`
`249
`
`Tc.:td1ing and Research
`
`2fi6
`
`SafCty of Bovine Gro\\•th I-lormone: 1). S. KH.ONFELn; J.C. JUSKl'.VICll AND
`C. G. Gu\T.ll Ill Interpreting C:inccr TcsL<;: J. f), \.YJL'>tn.,.; (~. VV. G!UBBLE liJ
`Kidne>' ·rran~pi.lnt;Hion: Overlooked Pioneer: G. B. Ei.roN
`
`26~
`264
`
`The Rush to Pnbli.sh fl1 lxssons fro1n Physics
`Third Strike for hbho Reactor
`CDC Abandons Pbns for AIDS Stuycy
`Healy No1ni11atcd
`265
`GAO ;lnd DOD Get Into a Cat Fight
`266
`Scicw.:c Liter.Ky: The Ene1ny ls Us l\l Science's 'l'op 20 (-Jrc.tte:;r Hits
`lll~Bt1!~ 268 New Light on \\'riting in the ArncriclS
`i\.Iontagni1.T Purswc.~ the J'vlycopl.t~nu-J\JI)S Link
`271
`Dc.~pitc Reports of ft.~ f)eath, thl' Big Bang Is Sal<:
`272
`GJnb.11 Tcrnpcr,uurc J lits Rcnird Again
`274
`Hli1~/iiig>: It1diation Rc<;c.trch Sh,1ke-Up f:l P1iv;i1e lniti<tti\'c on Fn,1l Jl.xsc,Hdl u
`275
`U.K. Ante\ llp for TekscofK'S u Ccorgc 1\•1.1.~on to Set Up Think Tank
`- - - - - - - - - - - - " - - " - - - - - - - - - - - - - - - -
`
`Subsistcnc~· Econon1y of t~l P<tr;1i\o, an E;1rly Pcruvi~1n Site: J. QtllLTEll,
`n. ()JEDA E., D. NI. PE:UlS1\l.J., D. I--1. S,\ND\YEISS, J. G. JoNr·.S, E. ,\.\. \\'n-.'.n
`283 Chc1nistry ,1nd Biology of the fm1nunophilins and Their Inununos:upprc.~sive
`Ligands; ~. L. Sci rn.1u11ER
`
`283 CCAAT-Enlrnncer Binding Protein: A Coinpouent of a Di!frrcntiatinn S\vitch:
`R. ~1. UMEK, A. l), P1uEDMAN, S. L. McKNIGllT
`
`29~ An Anti1nony Sulfide \\'ith a 'l\\•o·l)in1ensional, lntcr.~ecting Systc1n of Channels:
`]. B. PAlll~E
`
`SCIENCE QSSll 0036 Btl75) Is puh!/~h~d w~c~!y 011 Friday, QiCCcpt HHl lasl WNk In Oecemher, byl;;-;;-A;nar!can -
`/tssoclatlon fo1 Iha Advanc~manl of Sc!anco, 1333 ti Street, UW, Washington, OC 2001)5. S0>.:01id-<1.J5.s poS!.><JO
`(puli''(-,,lbn No. 4~1160) p-Jkf QI Wn:;h!nglcn, CJG, rtnrf ad.J 1:·~11~1 ir·a!~~g r,!fc1"s. Cop;~lght D lmo bi' the AmN;c_;i11
`/l.swci3!cn for tl.e A•J/ml~t"!m£>111 of Sc;er-(·~. TI'll t:!lu SCIHICE ~3 a rcffi!ered hildNil.~fl<_nf lhB AMS. Ourn'l~'.i.::
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`11·tf<J;I 21.c,;iunl n.·mbm. Po~tnwstur. Srn'J Chil·10il r•f M-:!r">s lo Sch'n:u, P.O. Ek>x 1723, m1crto1. flJ OUCl/l. Si11ulo
`copy aalos. S6 00 p('l l;sue pr<epP.·~ ind,,d,~ W'L'c" ~-<.d~qa, G1.'de t·J Bi~tc•:lrno'DiJJ' l'rcdL·ct.; "~d ln;trncr>;nl>, $20
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`5,110 pN p:•J~ /; p.<v 1J1n'I)· 10 CCC, 2l Ccn~1e ;:; Slrtcl, ;;~~""'· l.l3so,,ch·;1~lh o 1970_ llLe ;di;nt-licJ.1'00 {c,r!o f,g
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`'(-'~·rec 1rl h1rnic•n f!Oh•e~s
`
`SC!l+H:E, vn1. J.f,]
`
`Roxane Labs., Inc.
`Exhibit 1012
`Page 002
`
`

`
`·--------- - - - - - - -
`
`l.akcs and pond~ 011 t!w :trni• 111ndr.1 \\'ith ltig.1knit 1Y1ount<lin in the
`C:OVEtl
`b:lckground, North Slope, Ab~ka. The~c aquatic cco~y~h'lll~ •lrc continuously
`rc\c,1sing carbOJl dio.\.idr.: to thr.: ;1\1nn~ph1:rc. i\.1uch of the'. c.uhon orit~inatcs in
`tern.:\trial e11\'iro11111cntf'i, ,1nd accounting t<)I· this release .H1bst;u1tially lo\VCrs the
`c,~tin1;Hc of1hc \Vqrkhvide arctic siuk li.H at111u~pheric carbon dioxide. Sec p<1gc 298.
`{Photog,L1ph by George \V. Kling]
`
`294 Loc1I Structure :u1d Chc1nic1I .Shill:.s for Six-Coordinated Silicon in I-ligh-Prcssurc
`i\'1antlc Phases: J. F. STEBBINS 1\ND IvL K,\NZAKI
`298 Arctic l.;tkcs and Strca1ns :t~ Ga~ Conduits to the Annospherc: l1nplications for
`Tundta C:ubon Budgets.: c;. \V. KLTNO, c;. \\I, Kil'l'J-IUl', M. c. i\1ILLER
`30l Putati\'c Skdetal Neural c;n..·3t Cells in Early Late Ordovician Vertebrates froin
`Color-ado: i\·l. i\•1. SMITH
`303 Altered Perception of Species-Specific Sung by Fe1nalc Birds After Lesions of a
`Fo1-cbra!11 Nudcu.'>: E. A. BRliNO\VlTZ
`305 The E!lCct of Anti-Neoplastic l)rugs on i\·Iurinc Acquired llnn1unodcfi<.:ic11cy
`Syndroinc: C. SJ,\11\RD AND P. JoLICOEUR
`308 Evidence for Bi;l<icd Gene Convt't.~ion in { :onccrtcd Evolution of Riboso111al DN1\:
`D. fvl. l-hu.1s, <~. i\ilon.rrz, C. A. PoRTEft, R. J. BAl~ER
`310 The EHCcl of the Floor Pbtc on P~Htcrn and l'obrity in tl1t· l)c\'dupi11g (.;cnt1;1\
`Nervous Sy:-.tc111: S. l-l11tANO, S. l'usF., Ci. S. SoI-lAL
`31 :~ Rrg\1btion of Intcrkukin-2 l'""icnc Enhancl'r Acrivity by the 'f Cell Acccs<;ory
`1\1okculc (:1)28: J. D. FR,\SElti B. A. illVINl;) (J. ll. c:RAHTLUlE, 1\. \VEL'>S
`~~f?;~Yr~Jmrm!iJDfliIWiflll--3-lc-,--iv-l-ic--n:;,-v-c-S_o_u_n~ling llnits and Cltn~)-;\l_W_"_"_ning: lL L. CiAllY r\ND S. J. KEIJL\1;
`ll. \V. SPl~NCEll 1\ND J. R. Cr!lll.\l'\' Ill Lipid Flo\\' in Locornoting Cdh:
`Nl. S. B1li-:·1scJ1ut; K. J.\CoHSON, J. LEE, 1\.L Gu.'>-rA1°.ssnN, K.-E. l\·lA<;NUSSON u
`B1:1010,111 1\'\nrphologicll •tnd Genetic Correspondence: \.Yhat J)o{\~ [t Prove1:
`J. LEVlNTON; J.B. c. JACKSON ANIJ A. 1-1. CHEETl-Jt\,\I
`
`Autho1s of Their ()wn Live.~> 11'11i(·wcd by:\. SICA m 1\ustralian Ecosyste1ns,
`1\.1. LOV/i\11\~ tJ Tho1lan1ic 0$cillations and Sign:1ling AND Brainste1n Control of
`VVakcfulncss and Sleep, c:. Knc11 l!i Hooks Received
`
`32B Protein lnunnnoblotting Incubation Rotator Ill i\·1icronrnnipubtor 'l~1blc 111 Leiden
`lvlicroincuhator m Frcci'jng Stage \\'ith I'vlinotontl' ll l)ata J\11;1\ysis !Or the
`t\·lacintosh ti lvionnclon,\l 1\ntibodics t:J Literature
`
`llo11d of OJretlo1s
`fl', k11d u AtHns.cn
`ni.llrirg Prcs'dont,
`(,\l{l..-//OlillJ
`
`Dr1•i;,f<J N. langentiorg
`""'~.C,•nt
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`f'i•-'ii!C!l) P.'Cd
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`Mary Ellen /wery
`Franc:~o J. /\ya\~
`CugN'.O H C'.nl;1·Flt:!,!,.i,
`Robo1! A Frosch
`Josep'l G. Ga•.in, Jr.
`John H. Gilii:xlns
`Be<il<ij A Hnrnl1uro
`Florei~rn P. Ha>t-::1~a
`
`\'M'.irn T. Clo!<.kn
`r"'"'"'rer
`IHha'd S. tl(ho':on
`E<t:U!lirnOf'i.«v
`
`Edlto1rar Board
`
`Char!<::.- J. A111\ivr1
`Hiab~th E. (biley
`Da;~O Da't'ffO!O
`W1linfll F. EVinkrron
`E. l.l.1:gc:.1-0i Uu1b'd']et
`Pierre-G!fos de Gert<".('S
`Jo~<Jpl1 L Go~d~t<J-fl
`Ma·y t Gxd
`Ha'ry 11. Giay
`f_ Cl!lrk ll<"mr·'I
`Paul A. M;i.1~~
`Yawtorni t!isl'lrnko
`He'en /,\. llaww;·
`HoNard A Sct1n(·:de1m.~n
`Ro~erl /,\. SC!ow
`Edna(d C. mono
`J;i.1nes D. Wabun
`
`UoJrd ol Hevlo1~\ng
`Edi!ors
`JL•hn Nrnl5'Jn
`FrOO~rK~ w_ A't
`Don L Ander~on
`Stephen J. Oer>ko·{c
`c;,.,,t.;r l<-J H!vbd
`H<'.iid !O 131'.-.Jrn
`Herny R. Bou1no
`Ja1r_es J. Eu'J
`f(HTll')'ll C~l~ltHJ
`Cr1a1lo;; R CMi\C/
`Rri'p•1 J C'cerono
`Joh'l M Co~·n
`f1,·l.\.·1lD"'fmlr>
`£J!U<;V F. E:drl:l(/l
`P;it.\ T. En',)'und
`Fred:ic s. ray
`
`Harry A. Fou;ud
`The<Yjore H G\'bato
`Ro;itr I. M. Glass
`Steph~n I'. Go'f
`Cnre1 S_ Good•1un
`Slephen J. Gould
`E1b F. Jolln~on
`8!ephui I.I f(o:-.slyn
`KffNC!<.1 B. Kr<0Uslo.up!
`CnJrlos S l~~ ng;; Ill
`Rch,wJ lnoic.\
`J(lh'l C. ,,~cCrtf
`A!1ll1·""Y' 11 M""""
`1.'.-0rt;rner l,1ist·~·;n
`nx;w A. N:cdl
`\'.i!am H. Q;ff.e-,lohri-,on Ill
`G111 o_ raw
`Y•ist0ay.1u Poi;ker
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`Den11is A f'owar5
`ErHl Ruo;1at1ti
`H1omas W Sch')(·n~•
`f\on:·ld H. Sd.NJJlZ
`T eucnce J. Se/.vr.oVi
`Thn<l'"-S A_ Stetz.
`flolJ~rt T_ ti. T1;an
`Em~ R Urnnuo
`Gce1atJ Vemc<:j
`Oc11 VOjJcls1eln
`fh1.:.1d v1e:i-,11alJli
`ZertJ. \'/~rb
`Ocur&<l P,1, Whteoldt·s
`Om·n N. \'{•11"
`w, l .tm £J. Wood
`Keith Yamomo:o
`
`lH )1\NU.\ll.Y 1991
`
`·r1\l\LE Oil CONTENTS
`
`2.45
`
`Roxane Labs., Inc.
`Exhibit 1012
`Page 003
`
`

`
`This rnaterial may be protected by Copyright law (Title 17 U.S. Code)
`
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`!'_ l.1111llll)~, /'"" /.'o:f<'1<' 1/r,· fo(," (l'r.:rnL-~··llill, l'n~k1•:<w1l Clitl<. NJ, 1'1(11)
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`r c· !'.1!ln"'11, i11 /'"/1i;1,,1i1 .·l~1f,11/lr11,, S .. ~trcuwr, Ed. {NJ1111.d lli't'"I' l'"-'"
`(j_u,kn City.1\\', l'J7l_1, pp. !81 20H.
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`l\. l"ung l'., ,·lpw!l«-' ,-!r.J•l«'I. 2. l l ( 197 l).
`/.I[. S1,·11·,11J J1u! L. C. l-.111>11, N,1111·,· /''"l':cs ,fS,•:,1l1.·lm,1i1,, (;\hGr.m I !ill, ~~11
`\ OJ!L. l'J'.i'J).
`!:. \\. []_ l',lT'Ofl', ,-j.,._ ,-]11/i•/· ,i5, J,<)2 (19/0).
`ll. ). \\'1l"•ll, ,-],.,_ ,-lnr/11"/°''I- /l3, 9.i (l'H!l)
`Ill. f .~. llJymond, Aw. A111i.1. ·16, g()(> (1981).
`1- (~uillcr Jnd T. S1od . .:1, At11 .. ·l11//1"'I~'/. tt5, 5·~5 (1983).
`I J
`I~ I (.~uilt,-r, _/. l'idd .·\";.,:,·,•!. 12, 279 (1985)
`U F. A. Fngd, J- S,-.,-, .·lm. 55, 43 (1966); An.ii. Cini. lluii-. "\\'"''i'-' 5, :!.Jl
`'.19(17).
`·\ Od111r11, iu /',1r '/ J,,._,,y H,,i/dii(>.; iu .•!1,-/1-u.1 /,~\'i'• L Hinfur,l, fal. {1\cJdcmic l'r~\'\
`:Xllw Yrn>., 197/), pp. 157--24J.
`\. tluiltcr .111gg<'-<l<'d this p.:11,ihilit)' •luring work .H the l',1lo11u Sil<' in 1976.
`}!1
`/'1,u1,11.dr C'ulwrc· irt '1'1,uui1i1•11, Ta,·nH'
`16 C E Smiih, iu /_,, <;.1(::.1d~ p,,m,
`,•1
`(;lieder <1,1/., fah. (Univcr,ilJ' ofTn.1\ l'rc,s, Au~tin, TX, l9.S8), pp. 125-151.
`l/ 'i. l'llll\r,ki .ind T. Pou11~ki, g,,/y St11/.-m<111,ml S1iluiJ1t1u.- hr 1/1<· C.u11M V.:>11'1',
`/"'111 (Uniw-r,ity of lt111·l Prn~, Jowl City, 19S7).
`l:L \'. l'opp:.'r, in L<'-> Gu•i/,,,,,,_,, ,\for, Duirrl•' y 0.hi-> rn "1 IUilNi~ d.-l lfomb1.-, I>.
`!lon!1'i1, fa!. (Editoiiil Amoui.i, Umo, Pcrn, 1932), pp. HS-156.
`,\_ l'ou>r'<l-:i .tnd T. l'owiski, t"i111L G1111t:\'fr ,\Ju<. N,1/. HiJI. 49, 337 (1979); J. I\.
`l\iul, .;l111/r1,1p.,,/ "''J'· /Im. M11s. N,11. lli<t. 62 (19/\S), put l.
`)l). 1\ G1oh111.1n, in l.M (;,wi/,1110. ,\for, Di'ifrrl.:> )' (),!Jir«ll /,1 /li<l"1i-1 Jd lf.>ml"'\ D.
`
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`Ho:11\u, Fd_ ( bl1tt111.1I 1\thoui 1, I inn, l'c·ni, 1982), pp. lS?-179; H. L. llu11~cr
`\,m dtl .\h !\'.<\ • 0l"1 __ •\m.'u.>p<'/ 9l, ')6 ( l991J).
`J11d N
`·11 T D!l~rh.w, I'. Ncthnh', J. llo;1c•i. ,\111. ,]miq. 5·1. 7.B (1989).
`22 ), Quilt<r. "Til _ti<h !11 the• .1fkm•~lll: llL)'<llll\ Mll»i,tt'nc·c C<<>!um1i,·_, in rhc 11\H\)' of
`LJ!I)' A11(L:Jn ,11;1,1.11:0:1," f'lf>-.":r 1•1(1(1ltLd J! 5 l>r 1\1111u.1I Mc.:ii11g nr11ic Sn. it·1y
`!i>c A111c1ic.rn ;\nhtcolug)', Nell' Orlnm, I.A, 2.~ April 19~(>.
`2:l. t\l. ,\l<>'dq•, />,,-.,N,;.,,/r,mi/ (_\>.Hid/ Ci•'iliz.uic>m ill P(lll (Cuoliru l\iu!Dgy Rc.1d(cid:173)
`l'r,, 110. 90, H111lingto11, NC, 1978).
`24. j, Qui ha, ''( :.nc· .ul<I p<: ripl1<·1y in 1'1 <cci .irnic <,OJ't,1l l'r1 ll," p 111>:r p1c~c111«I .u 11,.·
`88th A1mu.1l /\kc1i11i-; of the i\mnic.111 Anthropu~ogicJ! .S1xict)\ W.1>!ii11i;1n11, DC,
`!9 Nmri11ho 1989.
`!C (;, Wilkin">n, /'•"'<II)' ,,,1,/ /'r••.•r,·•_< (Pr.>r{~<'r, Nnv Ymk, 197.i).
`2!>.
`26. Fu\luwint; t.ni li,1.-.! i11 V. Al.ui\O \I. and V. V.i!divic·10 M., [),>/,/, hut. ,\(,u />a1j
`(\'<!lumrn .:xtr;iordinni•1. ('...1llm, Pcn1, 191l7).
`27_ l'umling- for the El f'u.11\n n'11:.ird1 WJ> pr01·idcJ by NSF gtJnt !IN.S·R~.(13680,
`1-lipon Cu!lq~c FJuilt)' Dcl'clupmcnt f.\rnd.1, .m<l 1hc Contiucnul Colfr.: Product~
`Compm)' (J. 11·holly owned ,,,J,,i<li.iry nf Q1utn 0Jts). The nc11•Jtimt\ wc1c
`cJriicJ out under Crcdc1Ki.il 038·BJ-DCIR!lM, i1>11<d by the luJJil11/t1 N~rh11n/ i!t·
`C11/h1M ofl'c!ll. \Ve th.1.nk:A. A. lluntu (,\li1muri) who identified 1hc HJUt1h ~a,!1
`;iud ,\, 1'1icc, J. Attcl>.:u)', ,1nd L. I laub1id1 who hclpctl iu 1mting and t.11lyi11g d.11.1.
`Additimu! .ii,\ in pwce,,ini; th" '11b;is1c11c.: rn111iru 11·J1 )',i\'cn br N . .S1b-,4r .md
`M. C. RuJrfp1t·1. tic S.111d11ci~s in l'nu. I. .S1l11.1r-llmga. llii1um fidd dirc<rnr,
`11 .ll C>'CUliJl tu the pn>jt'ct. 'lh•: C1111r,1 J,- b11'<·;1(>:.l(i,;1:fj ,!( /.,;1:<1> A1Ji<U W!> our
`ln1c nfopoJti(m> .iml Jrulpi> am! w.: tli~nl. F. 1\. Engd ~ml M. V.1\kjo~ and lllJll)'
`ntll{r l'<'mVi)n cnlkgm~ for mppwt.
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`(~heJt111istry and Biology of tlhe Im1111u11rnopl1ilirlls
`ar11dl 'I'l1eirc I111n1ll1LllfllOS1L1p1prcess1tve IJ1~::u_1ds
`
`STUART L. SCHREIBER
`
`(:yclospodn A, Fl(506, and 1·apa1nycin are inhibitors of
`specific signal transduction pat11,vays that lead to ·r ly1u~
`phocytc activation. 'I'hese in11nunosnpprcssivc agents bind
`\Vi th high alJinity to cytoplasntic receptors ter1ncd inunu(cid:173)
`nophilins (in11nunosupprcssant binding p1·oteins). Studies
`in this area have focused on the structural basis for the
`1nolccular recognition of in11nunosupprcssants by inunu(cid:173)
`nophilins and the biological consequences of thcit· intel'(cid:173)
`actions. Defining the biological roles of this c1ncrging
`C11nily of r1.·ccptors a1ul their ligands n1ay ith1111inatc the
`process of protein tratHcking in cells and the 1ncchanis1ns
`of signal tr;.111s111ission through the cytoplas1n.
`
`·~lESEAllCH DURING THJ,'. l'A.'>T DECADE HAS CONTl\11\UTED
`significintl>' to our knowledge nr T l)'1nphrn.:ytc function.
`. ~~
`The identilicnion and li.111ctiou,1l ;urnlyi:i~ of T cell surface
`
`li_
`
`1n::cp1ors (/) <lnd nudc.1r 1r,111scriprion factors (2) h<l\'l' 111adc dic'ie
`co111punenl.~ of tlw signod tr,1n»dw.:tion :1pp.1ratu~ a1nong the bc.~t
`u11dlT\t1irnl in hiulogy. 'rl1i-; 11ndc1:il;111ding is bl).;dy due to thl' tl\l'
`o!' prob.: rl'o1gt·11ts, ~uth a~ lll(JJHK!on:d antihudil's and 1adiol.1bdcd
`rntclcic .1cid~, tlut have been devdoped frll· the studr of ~tnfau: ;1Hd
`1H1t·k.ir plll'11011w11a, re~pcctivdy. I-Iowevcr, tlw tlll'chanisn1~ for the
`11 .1n.~duction of sig11~1ls 1hrough die c~·tnpkls1n, the "hLtck hnx" llf
`tll(' ~ign:1l tr:1tl'iduction p,uh\'.':1y, re1nai11 n1y.~terious.
`1\ fH11ily of n.nur;tl prud11cts h.1s cn1crgcd ,\.\ probe reagents f(lf
`1 vtopb.\tnic sig11.1li11g 11wch,1ni.~1n~ in the T lyinphocytc. Th~·sc sn1all
`
`·111~ .1uthur 11 .1 prof<'·'''ir of Ch(1nisny, I lMv.1rd lli1l1·.:11it)', Cm1Uridg,·, ,\\1\ 021.lH.
`
`n1olec11lcs arc in11nunosupprcssants that <1ppear to exert their inhib·
`itory anion~ di~1:d 10 early 111c1nbrane-;1.~soci:ncd c\•cnts :ind proxi(cid:173)
`rnal to nuclear processes . .Studies on;\ fa1ni!y nf in1111unosupprcssant
`binding p1otei11s, tl1e i1n1nunophilins, h<lvt ;Utcntpted to idcntil)' the
`strw.::tur,11 rcquirenwn!s for high·allinity interactions between inunu(cid:173)
`nophilins and their i1nnn1nosupprcssi\•e lig;uHis and the binlogic1I
`consequences of the tClrn1.11ion of inuuunophilin-ligand complexes.
`Although there is n1ud1 10 explore in this a\'enuc of rt·.,.c;trch, sonic
`genen.1! principle:; i1ssociatcd \Vith the intern1cdi~1ry event.~ of.~ign,11
`processing arc c1ncrl~ing.
`
`The Immunosuppressants
`
`0
`
`Cydospurin A (C;sA)) an inhibitor of'f cell activation, is currently
`the fovotcd thcr;1pcutit: :1gcnt fOr prevention of gr.tit rejection alte
`r
`organ and hone n1arro\\' transplant,ttion, and it has been credited
`with initiating a revolution in clinictl tr<HVipbnt.Hion (3---5). The
`recently disco\'cred coinpound FKS06 inhibits T cell ,Ktivation by
`n1ccha11is1ns tl1;H a1c .~iinibr t<i tho:ie ofCst\ hut FK506 is 10 to 100
`tin1es :ts potent (6). FKSO(J h,1,; perfornwd ren1<1rk.1hly well in initial
`l1t111i;111 di11ic;1l transp!ant.Hion t1ills (7, R), tkspite reports of roxic
`dkrts in aninuls (6) Rap.unycin inhibits T cell .tctivation at
`lOl\Lt:1H1:11iu11.\ co111p.ir,1blc to tho~e of the structurally rel.ucd
`FKS06, yet with 1ncch:1nism<; tholt <l\'l' Hrikingly different from rhnsc
`nwdi;tted hy FKSOfi, ;tnd thu~ C.,A (9). ()nly c_:"A, FK506, ,\Jui
`r.lp.11nyci11 ha\'e been used l(ir the idc11tilic11ion of 1ncn1bcts of the
`in1nHJJH>philin cl.1ss. A non11,11tira! ligand, 50(iBD { 10), aud :1nalul~S
`of CsA (11--JJ) have ;\Jso provided in.~ight.~ into the inhibitory
`1nech:1ni~n1s or in11nuno.~l\J)prl'SS.llllS. Many recently di.<;covercd
`i111n1unosupprc:>sivt· agents {/'I) \vitl111n{kflncd nKrl1,1nis1ns, snch as
`
`la )1\t~UAl\\' 1991
`
`AltTICJ.J'.'i
`
`2HJ
`
`Roxane Labs., Inc.
`Exhibit 1012
`Page 004
`
`

`
`discodcnnolick ( 15) and deoxy~pergu.tlin ( 16 ) 1 promise to n:ve.il
`new facets or cytoph1.sn1ic sig11~1Ji11g !llt'chanisrn~ ( /7) (Fig. I)
`
`The lmmunophilins
`The prcdo1ni11ant C'>A-hinding protein in ·r lpnphocytcs i~ tht·
`.'iOlubk, cytosolic receptor cydophilin (18,
`/9). <=ydophilin is an
`abundant and ubiquitous proKin th.n is fr>und in both prok;uyntic
`and cukaryotic org.tnis1ns. The nujor isofOnn of lnunan cydophilin
`has a mas.s of l'/,737 da!tons and an isoe!cctric point (pl) of 9.3.
`'I\vo groups have independently reported that cydophilin is identi(cid:173)
`cal to peptidyl-protyl iso1ncrasc (20, 21), an CllZ)'tne th;ll catalyo:s
`the interconversion of the ds- and tr,111s-rota1ne1s of the pcptidyl(cid:173)
`prolyl a1nidc bond of peptide and protein substr;\tcs, and this
`rotan1ase ac1ivity is potently inhibited by CsA.
`Shortly after this disco\'Cl)'• the prcdon1inant FKS06-bi11di11g
`protein in c.11f thyinus, hunrnn spleen, ;u1d the ·r cdl line Jurkat,
`lcnncd FKBP, \\'.ls i.~ol;\lcd ,u\d clur.u:tt·rized in t\vo labor;ttories
`(22, 23). Like cyclophilin, FK1JP W;l~ sho\vn to h.wc rot-.11n;1se
`aoivity t{J\\'.1rd a peptide suhstr.Hc. FK506 inhibits the rot;11nase
`activity of FKBP, but not of cyclophi!in; !ikcwis<:, <:~A dues not
`inhibit the rot.1111asc .Ktivity of FKBP. The doning (2•J, 25) ;111d
`OVt'rt'Xpre.~sion (24) of !111m;1n n:co1nbin;ult FKBP ;UHi the clnning
`of an FKlll' fro1n 1\!r11r11s1wi.1 Oiu.rn (2fl) n~\'l·alcd th~ll, despitt" tlll'i1
`con1111011 e11zy1natk pro1wrtit·\, FKBl' and cydnphilin have dis~in1·
`ii.Ir 1-t'tjlll'llCC.~. H urna11 FK n p h.1.\ ;\ 111.\.~~ of 11,819 tb!tons ;u1d, like
`cydophilin, is a ha.~ic (pl ::::: 8.9) (22, 2'1), cytosulic protein (27). A
`proka1yotic organism, l\ldssc1i11 mn1i11gitir/i,, \\',ls ltiuud lO have ;11i
`open reading fr,une that cncod<:.~ .111 FKBP-likc protcill (2'J). 1\1ort'
`tcccutly, FKBP \\',1s sho\\'n to bl~ the prcdo1nin,u1t r.qi~unycin­
`hinding protdn in yl'ast, ctlf thynu1s, and hunrnn T cells (JurhH)
`(l.H). Rap,unycin (dissociation t'onstant Kd = 0.2 rn\1l) h;1s ;in t.:vcn
`hight.:r afiinity for FKBP than doc.~ l'K506 (K,1 = OA nlv1), and is
`also i1 potent inhibitor nf FKBP's rot.unast.: activity (inhibition
`
`COJ\~C<lllt J<., = 0.2 111\•l) (29).
`Although cydophilin ;ind FKBP ;1.fC the only wcll-ch,1r.1cttri1,cd
`in1n1unopl1ilin<>, ot!i<:r 1ncn1lH:1 s of tl1i~ fa1nily arc known lo c.xi.~r ;111d
`;lie curicntly lit:ing invcsrig<HLd. For c.xarnplt.:, a C.'.st\-hinding pho.~­
`phoprott'in of rc!ativc 1nolrcubr 1na~~ (i\1,) 4S,OOO has hecn tktcc\(cid:173)
`cd in Jurkilt cells (JO), ;Uld phosphoprotcins ot' 1\-lr 60,000 ;ind
`80,000 fro1n thi\ s.une cell line bind to both FK506 and r.lpa1nydn
`(28). The 11i11rtll gene of J)ni,<oplii/,1 (31, 32) and a :,econd cycln(cid:173)
`philin-rclaled gene in So(d111f"Oll!}'fl'S Cl'ft.?l'isial' (JJ) encode prokin~
`that :,how high hornology to cydophi!in. Sc\'cr,11 k)\V 1nokcnl.1r
`\Veight, h.1sic proteins that ;trc 1ctained OJI C~A, l;K506, or f;lp.l·
`n1ycin allinit}' 1n;1triccs have ;1lso been noted (22, 28). P.triial
`sequence: dctt'nnination of FK506- and rap;unycin-binding in11nu-
`11ophilins of A'1r 30,()00 and i\1r 13,000 has rc\'cakd that thc~c
`n1o!ecuks, tt1gethcr with FKBP, arc n1l·1nbcrs of a prcviou~ly
`unknown fa111ily of inunnnophilins (34). Que.~tions concerning 1hc
`biological relevance, the rota1n•He :l.Ctivity, and the affinity to the
`cognate ligands of these lo\v-abundance i1nn1unophilins should ~oon
`be ans\\'crcd.
`Although the exact cclluh'r concentrations of I•KBP a11d cydo(cid:173)
`philin arc not kno\Vn, both arc abtut<.bnt. .S;tturation binding in thl'
`c~·to.~ol of J111"kat cells "'as reported lo occur at > 5 rn\tl ditril io(cid:173)
`FK506 (27). 1\s FKBP is the prcdo1ninant cytoso!ic receptor li:Jr
`drug, thi.~ n1e;1H1rement is !argcl>' accounted for b~, i-;KBl1, ,\nd 11111'>
`the tylopbs111ic conc-entration uf FKBP n1.1y appro;1ch 5 ni\'1. The
`high-afllnity FKBP Jig.1nds FK.106 .1nd r.ip.l!HJ'Cin, howe\'cr, inhihi1
`T cell pn1lifcr~1tion .u subn;11101nohr concentr.uions (1nedian inhihi
`ti on concerll t ~uion I C.su -, U. 5 111\'l) (29, J5). Therefore, in hi hit ion of
`the r0Lu11asc acriviry or FKBP is very likely an in'>ufilcicnt require·
`n1cnr for n1edi;1ting the ilCtions or these drugs in T ly1nphorytr.\,
`hl'c;n1se only ;1 sn1all franion of the cnzyn1c \\'ould ht.: inhibited at
`dfrctivc drug conc-t·ntratio11s. Thi,s point ha'> been confinncd hy
`111cdunis1ic studies of FK506 ;u1d Llp.unycin (sec bclo\v); likcwi'>(',
`investigations of C..\A ;1nalogs support a .~ilnilar conclusion rcg,uding
`the rcitan1ast.: anivity of cydophilin (/2).
`
`CsA
`
`FK506
`
`50600
`
`'"
`
`It O Oil o
`
`"m•, o ~£
`
`(~/~(''•
`0
`'.,~-/"-'""'~o 11 •
`i~.
`'~• on. ii.
`
`(___,.,. ···011
`
`Oisrod~ru1olidfl
`
`01m>:yspcrgualln
`
`Fl!J. 1. l'rolil' rc".lgl"llt-" of imr.1Cdlul.Ir ~ig11.1li11g p.1tl1wJy~. (A) Rcn~ntly
`io\'C'•lig.11nl immm1ophiltn lig.1nds. (B) lmn11mo.<.upp1o~i\·c .ignH' with
`uuknow11 11w..-h.111i~111~ of"J' ..-di inhibition. [!Vic\ 111-:th)'L)
`
`Molecular Recognition by the Imnnmophilim
`The rornn1;1sc activity of 1hcst.: i1nnnu1ophilins ;UHi the ability ot"
`their i1nn1unosupprcssivc ligand~ to acl as rot.1nia~t: i11hibito1s
`provide an opportunity for c.xploration uf tl1c 111ulcc11br basis frir tht:
`high-a!linity intcrncrions that exist bet\vccn thc1n. Initial 1neclrnnistic
`studies of cyclophilin led to the sugg(·stion that G\l<1lysis of the
`inten:onverf.ion of ds- ;u1d /r1111s~1ota1ncrs of a peptide suhstr.nc i~
`ad1icvcd by the frlrni~uinn or., t•ovalent bond to !he cirbuuyl of the
`p<:ptidyl·prolyl ainide with a cyslcinc-dcrivcd thin\ (36). Loss of
`aniidc rc.'lonancc \Vould he expC"cted to lo\ver the •lctivation h~111 il·f
`to rotation abont tl1l' ainide C N bond . .Site-directed nH1tagt'IH:si\ o(
`lnun.111 rcco1nbin.u1t ()'clophilin allowed tht• systt'lll~Hic rcplacc1111"111
`of ;\II four cyslcinc rt'siduc.'i in L)'clophi!in with alanin<:. lkcall~l' .111
`four 1n11t.u1t.~ cn7.yn1cs \\'ere fully acti\'c in rlit: rot.1n1~1sc ;1nd binding
`;1ss~1y.s, rysteinc \\';\.~ 111kd out a.~ ,1 p.1nicipating residlK" in cu.1ly.-;i~
`(J7).
`Addition.1! rnechani~tic studies with both crclophilin (JS) .1111!
`FKBJl (39) \trongly ~11g~c~t th.n these t'll7-)'ll1l'S cat<ilyzc roLnncr
`inter.:<Hl\'lT~ion hy l\OflCOVJknt stabiliz;ltion of the (\\'isted ;lmidc
`tr.tn)ition .~tntc ti:1r the nonc11:1lyzt·d i~onicri7,1tion. The :11n1dc
`functionality exhibit~ ;1 ,qrong prd"crcncc for a pla11ar geo1ncu y,
`whcrt·in the nitrogen lone p.1ir i~ in conjng.uion \\'ith the c.irhi)nyl
`-;r-doud. Th<: c1w1·gy co~t of the t\vistcd a1nide Mructnrc (Fig. 21\) i\
`l5 to 20 kc.ti (40). The stnICtural b.t~is fin· cyclophilin and FKl\P\
`.1bility 10 stabilize this tr;111~ition-st,ne stnKttltT rnust a\\';lit fur1he1
`s1ructoral an~1ty.~c.~ of rot.1n1,1~e-pqnidc (fir inhibitor) co111pkx~·s.
`
`.'i< "J!'/>.'.CE, \'01.. J~, I
`
`Roxane Labs., Inc.
`Exhibit 1012
`Page 005
`
`

`
`pn:.,entin~ i:d! n·.\ulL\ in thl· ;1i:tiv.1Lio11 0C;1 TCR <>ig11~1l tr.111srni~sion
`p.nhw.1y. The sign;1I is tr.u1sdut'cd thnii1gh thl· crtopl.1.'>111 by an
`unknown 11Kch;ir1is1n .u1d n·sults in the .Ktiv.ninn of.~pci:ific nuckar
`trotnscription factor.~, ~uch as nuclear foctor of ;1ctiv,1ted T cdls
`(Nl'·AT). These nuclear fonor.~ help to rrgubtc tht• tr,111\criptiori or
`'I' cell ;Ktiv.uion g<:nc,<;, such •l~ the gene of the ly1nphoki11e intcr(cid:173)
`!cukin-2 {l L-2). Tr.1nsl.ition of the result.int n1cs~.1gc is frillo\vcd hy
`sl'cretion of IL-2. Cs/\ ;1nd FK506 arc potent inhibitors of the
`·rcR-1ncdi,ltcd signal tr,111sdunion p.1thw,1y, ;1s evidenced h}' 1heir
`•lbility to inhibit the ll'i\llSCription or Lady T cdl Jctiv,ition gene~
`(44). c~A (45) ;1nd FK506 (29, 46), hut nor rap.unycin, inhibit the
`binding ofNF-A'l' to the IL·2 enhancer and inhibit tr;1nsrriptional
`activation b}' Nf-AT. c: .. A and FKS06 aho inhihit 1r.1nsrrip1ion
`1nediatcd by AP-3 and Oct-1, and partially inhibit tr,u1scription
`1nedi;tted by NF-icB (45, 4f.). Another ilht~tr.ltion invohTs the u~e of
`1· cell hybrido1nas tlut undergo a suicidal event c.1lkd <lpoptosis
`;1ti:er stinu11.uio11 of the 'f'CR-CJ)3 coniplcx. c:.<>A ;11Hl FK506, hut
`not r•ljl•llll)'Cin, .ire potent inhibitors of apuptosis induc<:d by ,111
`antibody to the 1'CR-CD3 co1npkx (29).
`T cell a(tivation involvt-.~ not onl}' IL"2 ~errerion but .-ilso cxpre.~­
`sion of rhe ly111phnki1w 1t•ccptor IL-2R 011 the ~urfacc of the tL!I.
`Aller the binding or IL·2 to JL-2R, a ly111phokin<: receptor (LKRJ
`sign.ii tran.~rni~~ion pathw.1y i~ activ:11t·d. Tian,ductinn of tJii, <>ig11~1l
`~\g,iin pi<KCl'th by an unknown nKch;111isn1 through the cy1oph.~111
`;u1d into !he 1lt1Cklls, WIWrt: ~I di!l;:rl'lll ~l'l or gciH"i i~ lf,\ll~Cl"iht'.d
`\Vherc.1s rnparny(in, despitt~ it~ structural .'-iin1ituity to FK506, has
`1H1 dfrn nn the production of IL-2, it potently i11hibit~ th<: 1r!>pn11se
`of the T (ell to I L-2 (2Y, 35, <//). Rap.unycin th\l'i appe.u.~ to inhibit
`;1 );Ht~r l.Klt-;1~\(Kiatcd signaling patl\\v;iy (Fig. 3). Bcctu~t· both
`n1pa1nyrin and I' K506 are potent inhibitors or the ro1,1mase activity
`of FKBP ;1nd inhibit distinct signaling p.nhways, these 1e~u1t~
`support the suggestion that the inhibition of rot<1n1ase 01ctivity of
`FKBP is an in~ullicitnt rcquire1ncnl !(Jr 1nediati11g the actions of
`FK506 and rnp;un~·cin (10, 29).
`In ;1dditinn to their ability tu inhibit dilll:n:nt T cell attiv,1tion
`events, rap,unytin and l;K506, but not c:~A, hav(' been shown to be
`nullua!ly inhibitory in ~I v~1riety of functional ;ls\a}'.\ (29, 47). These
`f('.<.Ulls suggest a role frw t•ithcr ;1 single inununophilin or separate
`inununophilins th;1t .~hare a conu11011 receptor site in n1cdiating the
`actions of FK506 and r;1pa1nycin. Futthcnnnre, rap•unycin can
`distinguish th<: biolo~ical ~Ktions or FK506 ;1nd C~A. ht:Clll~C it has
`no elfi:rt on the •lctions of c~1\.
`The 1nutual inhibition of FK506 and r;1p<11nycin was sho\Vn to be
`subject to a buffering action by FKBP (29). A co1Kt'ntration 10 to
`100 tiinc,~ the cffettivc drug conccntcuion (ICsu - 0.5 nfvl) of
`
`H!J· ?.. (A) 1\lodd of the 1r.1n~itio11 st.lie stnKWre ofa 1whted pcptidyl-prolyl
`:1rni1k bond th.u is sl.lbiliznl by the ror.1rn,1~e cnzynll'> q·dophilin .111d
`1-f;J\!'. (0) Sn!>~trunw1· uf FKSOf, :111d (C) (\1\ (ho1h fiuu1 .\·r.1y) th:H j,
`p1opo-;nl tn 111i111ic the 1wi~trd ,m1idr boud uf .i peptide ~uh.,11.Hc. (0)
`\11h,trudmr of FKS06 (ll = O,\kj .md r.1p.nnycin (R = H) pnipu>rd to
`,m1idc bo11d of ;\ pi:ptak substr.ltr. (E)
`;\ twi,tnl k11<.:yl-prolyl
`1ni1ni<:
`!.<'uq•l-prnlrl fr,1gme11t indicHmg .\ln1cnir.1I ~imihtritil'S to immuno·mpprc.'>
`,.1111 .,u[J,rn11.:n11rs.
`
`! lowl'ver, the unusual structure of the i1nrnunophilin ligands and
`pr,,li1ni11,uy strucn1r.d invt'.stig.ttiuns of th<: i1nnnmophilin-lig.1nd
`t-0111p!ex suggt'st :i b;1.sis for their rot.11nase inhibitor}' propcl'ties. The
`101.l[ synthc~is 01";1 1-'C-l:thclcd FK506 (·II) providl'd a reagent HJ
`c.H1y our 1.~c 11w:k;1r nrngnctic rl'Sonance {NNlR) studies or the
`Pl~S06-FKBP nnnpkx (42). It w.1s .<.11ggcstcd
`th,H
`the- ketone
`c.trhonyl adjact'llt to the ho1nopro!yl <Hnidc hond of FK506 (Fig.
`2B) and rnp.11nycin is a n1i111ic of the ;11nide c.ffbonyl nf a pl'ptidc
`substrate. Thus, FK506 and raparnycin arc rrnnsition-st:uc ;utnlogs
`in th;\t their ground·st-.1te gco1nctry is si1nib1- to the lr<uisitiou-st;nc
`SinKturc of a peptide .<.11bstr.1te (Fig. 2, A and B). Also, the .<;idc
`duin of the 1u1usu,iJ aniino arid 1\l-n1cthyl-butt'11y!thn:oni11e
`(;>,·lcBint) of (;sA, \Vhich is kno\\'ll to be esst·utial !()[· high-allinity
`binding of Cs A to C)'clophilin ( 11, 12), ha.'> structural sintilarity (fig.
`?.CJ to the aforen1entioned transition-state stn1cture (Fig. 2A). This
`.\id{' chain in:iy lit• a difli:rl'nt type ofsurrogalc fiH· th<: twi!>ted a1nidc
`qructur<:, In thi~ 1egard, the a-br.incht·d hydroxyethy!ene substruc-
`111n'. of CsA is rt·1nini~cc11L or the hydroxyi:thylcne .unide isostcn:
`ii111nd in ;1sp.1nyl prott'ilSC inhibitors such '1-~ pcp!>t<Hin,
`The an:ilngy of the t\·kl'tn·lHHllOpro!yl grouping in FK506 ;Hid
`; .1p.1n1y(ill to ;\ t\visft'(\-a111ide bo11d of a pqnidt· s11hstratc '''"''
`,·\tended (39). A ~ub.~tr .Ile tot1L1inini.-; .1 leucyl-prolyl dipqnidc wa\
`1( 111nd to lK' optin1,1I fi:ir FKBP (JY, '13). The structural sin1ilantic\ of
`I 1(5()6 ,Hid r.1p.1111ycin to ;l twisted kw..:yl-aruide bond (Fig. 2, l)
`:ind E) ~uggest these agents rnay bt: tr.1n.~icion-st;He analog.'> of ,1
`kt1<)'l·(t\vistcd an1ide)-prolyl peptide .~11hstratr fOr FKBP.
`
`'f:hc Biological Punction of Immunophilins
`Th<: con1plex series of events that nnnprist•s the T rel! activ;Hion
`(.1'-it"ilde (f,\ll'>pilT\ over St'.Veral dJys (2). c~A, FK506, and r.1pan1ycin
`.Kt \Vi thin (he first holU-S of the process (Fig. 3 ). Stin1ulatio11 of the
`T cdl receptor (TCR) hr foreign ;HHigcn prcs<:ntcd by a 111.1jur
`hi-.;tot·oinp<Hibility (J\•11-IC) 1nokcuk on the surfitcc of an antigen-
`
`lt< J1\NUAllY 1991
`
`AllTICLES
`
`285
`
`Roxane Labs., Inc.
`Exhibit 1012
`Page 006
`
`

`
`lrnmuno
`1nodu!alion
`
`A
`
`B
`
`Bnd11 \J
`dom;in
`
`Flo. 4. Sd1cm.Hic il!u\tr.uing the rl'l.lli\·c :1hund.11Kt' nf a•n·111or and lig.rnd\
`TIH" .dmml.u11 FKHI', whi.-h 1n.1y h.w,· .1 rdh1J.ir 11111L1illl1 ;h .1 fuld.t\t', i\
`CUll\'l'Ltcd tu au i11hibito1y compk.\ on hi11di11g uf the drug <llld buik1s thr
`.htiol1~ of the .1nt.1goni~t.
`
`citlwr agent i" rec1uircd \(Jr inhibition of tlw ;Ktinns of tlw other (29,
`47). Thus, the abundant (~-5 n~·l) uncon1pkx<'d irn111u1uiphi!in
`scqHc,lt'f.\ the antagonisL ()nly oilier the cxcc.<t<; binding .~ite.'i arc
`occupied does thl' conccntr.Hion of the ;Hlt<1goni?.ing agent risl'
`.~11flicicndy to di.\pLKc the drug dfrctivcly fron1
`iL'i biologic.11
`receptor. The-;<' tindings aho i1nplic.ttc the irnn1unophilin·dr11g co1n(cid:173)
`pkx a' llw inhihl!c)r nfT rd! arti\';Uion. t\hhough ~1 rnk fOr FKBP a.\
`the 1nt:diator of the biological actions of rapan1ycin and PK506 ha-;
`not hccn .~hown, the bu!frr dfr·ct of FKBP evident in the studies of
`reciprocal inl1ibitinn s!1ould ;\IS<> h:.- operative \\'ith co1npcling cellular
`receptors for thc.'i1' dn11~s. The !o\V-;tbundancc in11nunophilins n1u<;l
`O\'CILO!ll(' thl' high abundance or FKBP and its high aflinity fi.>r drug
`in order to coinpctc dfrctivdy !Or binding (Fig. 4).
`Invoking thL' i1n1nunophilin·drug: co1nplcx as the biologic"! cilCc(cid:173)
`tur .1ddrc,s;;e.~ the is~Ul' ofhn\v the ubiquitous l'yduphi!iu and FKBP
`could be involved in T rl'll ,Ktivation. One possibility is that thl'Sl'
`proteins have a 1norc gcncr.il function, pcrhaps assisting in protein
`folding in vivo by acting as fokfoses. ()nly when the inununophilin
`con1binl'S with it'i in111n1no~t1pptl'Ssivl· ligand does ir inhibir T cell
`~lctivation. Till' o:llul,1r i1111nunophilin receptor (possibly FKBP),
`bound to cithct· 1:K50(1 or r.1p.1n1yci11, nur interact with di!!Crent
`n1okn1ks in distirn:t p.ithways ofT cell activ.l!ion. Act"C>rding to this
`hrpothl'~i\ 1 the .~pn·ificicy llf the fartor.s ;1\~oLiatt:d with diHCn·Ht
`.~ign,1!i11~ pathways i1' detl'nni11cd by thl· ptTci<;t· gt:onwt1y of thi:
`i1nn111nophilin-drug co1npkx. Evidence h.1~ been prt:scnted ( ·18) th,11
`tile t'}'l [Dphilin·( \t\ uunpk.\, and 1101 C8t\, is the agent rt .. ,punsibk
`fr)r the 10,ic :inion~ of (:st\ 111 two lower n1ka1yotes. <:~A-sl'11.~irive
`,\tr.1ins of :'-7. OrH.i<I .ind S. ct•1e11i.;i,1t• \\ll'l'C gro,vn in the prcscn<:c of
`Cs/\. 1\11~1lysis of thc Cst\-rrsi~t.ult n1ut.u1t str,1ins th.u resulted
`1-cvt-.1lcd that tither tli1;y 110 longer p1odi1cnl q•doµhilin or, if they
`did, thl' cyduphili11 of the nlUl.\lll .~l1;1i11s did not bind CsA (48).
`The ronunon biological receptor site i1