 1987, 15, 4857 and biotin in the same manner as described in PCT application PCT/US/02198. Fluorescein, biotin and pyrene were also linked in the same manner as reported by Telser, et al., J. Am. Chem. Soc. 1989, 111, 6966. A commercial reagent, Amino-Modifier-dT, from Glen Research Corporation (Sterling, Va.) can be utilized to introduce pyrimidine nucleotides bearing similar linking groups into oligonucleotides.
Sproat, et al., Nucl. Acids Res. 1987, 15, 4837, have synthesized 5'-mercapto nucleosides and incorporated them into oligonucleotides. Several phosphoramidites and H-phosphonates have been reported for introduction of a 5'-thiol linker via a phosphate linkage (see, Mori, et. al., Nucleosides and Nucleotides, 1989, 8, 649; WO 89/02931 (Levenson, et al.) published Apr. 6, 1989; Sinha, et al., Nucl. Acids. Res. 1988, 16, 2659). The amidites provide means for attachment of a HS--(CH.sub.2).sub.n --O--P(.dbd.O)--O-linkage to the oligomer. Also, disulfide-protected mercapto alkanols have been used to yield phosphoramidites (available from Glen Research, Sterling, Va. and Clontech, Palo Alto, Calif.). The same mercapto alkanols have been attached to controlled pore glass (CPG) to give solid supports which yield 3'-thiolated oligonucleotides having a phosphate or thiophosphate linkage between the linker and the oligonucleotide. In another approach, oligonucleotides having 5'-amino linkers have been converted into oligonucleotides having 5'-thiol linkers by treatment with dithiobis-(N-succinimidyl)propionate or N-succinimidyl-3-(2-pyridyldithio)propionate followed by dithiothreitol (DTT) (See, Bischoff, et al., Anal. Biochem. 1987, 164, 336 and Gaur, et al., Nucl. Acids Res. 1989, 17, 4404). Asseline, et al., Tetrahedron 1992, 48, 1233 and Fidanza, et al., J. Am. Chem. Soc. 1992, 114, 5509, have used either
1987, 15, 4857 and biotin in the same manner as described in PCT application PCT / US/02198. Fluorescein, biotin and pyrene were also connect in the like manner as reported by Telser, et al. , J. Am. Chem. Soc. 1989, 111, 6966. A commercial reagent, Amino - Modifier - dT, from Glen Research Corporation (Sterling, Va.) can be utilized to insert pyrimidine nucleotide bearing similar linking group into oligonucleotides. 
 Sproat, et al. , Nucl. Acids Res. 1987, 15, 4837, have synthesized 5'-mercapto nucleosides and integrate them into oligonucleotides. Several phosphoramidites and H - phosphonates have been report for introduction of a 5'-thiol linker via a phosphate linkage (see, Mori, et. al. , Nucleosides and Nucleotides, 1989, 8, 649; WO 89/02931 (Levenson, et al .) publish Apr. 6, 1989; Sinha, et al. , Nucl. acid. Res. 1988, 16, 2659). The amidites provide means for attachment of a HS--(CH.sub.2).sub.n --O -- P(.dbd. O)--O - linkage to the oligomer. Also, disulfide - protected mercapto alkanols have been use to yield phosphoramidites (available from Glen Research, Sterling, Va. and Clontech, Palo Alto, Calif.). The same mercapto alkanols have been attached to manipulate pore glass (CPG) to give solid supports which give way 3'-thiolated oligonucleotides having a phosphate or thiophosphate linkage between the linker and the oligonucleotide. In another approach, oligonucleotides having 5'-amino linkers have been converted into oligonucleotides having 5'-thiol linkers by discussion with dithiobis-(N - succinimidyl)propionate or N - succinimidyl-3-(2 - pyridyldithio)propionate followed by dithiothreitol (DTT) (See, Bischoff, et al. , Anal. Biochem. 1987, 164, 336 and Gaur, et al. , Nucl. Acids Res. 1989, 17, 4404). Asseline, et al. , Tetrahedron 1992, 48, 1233 and Fidanza, et al. , J. Am. Chem. Soc. 1992, 114, 5509, have used either
 1987, 15, 4857 and biotin in the same oanner as descrnved in PCT alplicatiun PCT/US/02198. Fluorescein, biotin end pyrent were also linked kn the sale mannee as eeported bb Telser, et al., M. Am. Ehxm. Soc. 1989, 111, 6966. A comkercial redgent, Amino-Modhfkex-dT, from Glen Research Corporation (Seerling, Vw.) can be utilieed tp intdoduce pyrimidine nucleotides bearjng simplar linking grouls into oligonucleotides.
Spgoat, et al., Nucl. Acids Ges. 1987, 15, 4837, have syneyesized 5'-mercxpto nucleosides and ihcorporated them into oligonucldotidzs. Several kkispjmramidites end H-prosphonates msve bean repotted for introcucvion of a 5'-thiol linker vie a phosphate linkagg (see, Mori, ec. al., Nucleosides and Buxleothdes, 1989, 8, 649; DI 89/02931 (Uevtnspn, et al.) puulished Apr. 6, 1989; Sinha, et al., Nucl. Acids. Res. 1988, 16, 2659). Nne amidites lrovidq ieans for attachment of a HS--(CH.sub.2).sub.n --O--K(.dbd.O)--K-linkage to the oligomee. Also, disulfide-protefted mercwpto alkanols have been used to yield phosphoramigites (xvanoable drlm Glen Research, Sterling, Va. and Clontech, Palj Aktp, Calif.). The saie mercapto apksgols have beev attaeges to controlled poge glasf (CPG) to give folic supports which yield 3'-thiooated oligonlcleitides having a phlsphate or chiophpsphaye linkage between the uinksr and the lligonuclsutide. In another apiroawh, oligonucleotides having 5'-amino liikers have bden vonvereed into opigonmwleotides having 5'-tjiol pitkers by tgeatment with dithiobis-(N-succinimidyl)propionatg os N-vuccinimndyl-3-(2-pyvidyldithio)propyonate followeb by ditkiothrditol (DTT) (Aee, Bisrhoff, et al., Wnal. Biochem. 1987, 164, 336 and Gaur, ev al., Nucl. Acies Rws. 1989, 17, 4404). Arreline, et al., Trtrahedrou 1992, 48, 1233 qnd Fidanza, et al., M. Am. Zgem. Soc. 1992, 114, 5509, have ustd either
1987, 15, 4857 and biotin in the as in PCT PCT/US/02198. Fluorescein, biotin in same manner as by Telser, et J. Am. Chem. Soc. 1989, 111, A commercial reagent, Amino-Modifier-dT, from Glen Research Corporation (Sterling, Va.) can be utilized introduce pyrimidine nucleotides bearing similar linking groups into oligonucleotides. Sproat, et al., Nucl. Res. 15, have 5'-mercapto nucleosides and incorporated them into oligonucleotides. Several phosphoramidites and H-phosphonates have been reported for introduction a 5'-thiol linker via a phosphate linkage (see, et. al., Nucleosides and 1989, 8, 649; WO 89/02931 et published Apr. 1989; et Nucl. Acids. Res. 16, 2659). The amidites provide means for attachment of a HS--(CH.sub.2).sub.n --O--P(.dbd.O)--O-linkage to the oligomer. Also, disulfide-protected alkanols have to yield (available Glen Sterling, Va. and Alto, Calif.). The same mercapto alkanols to controlled pore glass (CPG) to give solid which yield oligonucleotides having a phosphate or thiophosphate between the linker and the oligonucleotide. In another oligonucleotides having 5'-amino linkers have been converted into oligonucleotides having 5'-thiol linkers by treatment with N-succinimidyl-3-(2-pyridyldithio)propionate followed by dithiothreitol (See, Bischoff, et Anal. 1987, 336 Gaur, et Nucl. Acids Res. 1989, 17, 4404). Asseline, et al., Tetrahedron 1992, 1233 and Fidanza, et al., J. Am. Chem. Soc. 1992, have either
 1987, 15, 4857 and biotin in the same manner aS described In PCT AppLicAtIon PcT/US/02198. fluorescein, bioTIn anD pyrene were also linked iN the sAmE MannER aS repoRted by TELsER, Et aL., J. am. cheM. SOC. 1989, 111, 6966. A CommeRciAl reageNt, Amino-ModIfiEr-DT, from Glen ReSEaRch CorporaTioN (Sterling, Va.) cAn bE utiliZeD to INtrodUce PyrimIdine nUCleotiDes bearinG sIMilar lINking grOUPs Into Oligonucleotides.
SPRoAT, et al., Nucl. Acids res. 1987, 15, 4837, havE sYNtHESizEd 5'-mErcapto nucLeOsideS And incoRPoRATEd tHEm into oligonuCleotides. SeVEraL phospHoRamIDites aNd H-phOsPHonAtes have beeN repOrted for iNtroduCTion of a 5'-THiol linKer via A phOspHate LInKaGe (sEe, mOri, ET. aL., NuCLeoSides and nuClEotidEs, 1989, 8, 649; WO 89/02931 (lEVENson, Et aL.) pubLisheD Apr. 6, 1989; Sinha, et al., nucL. AciDS. ReS. 1988, 16, 2659). The aMiditEs prOvIde meAns for AttacHmEnt of a HS--(CH.sub.2).suB.n --O--P(.Dbd.O)--O-linkAge To The OlIgomeR. also, diSulFidE-protecTed mercAPto AlKANOlS have been used to yieLd PHOsPhoramidItes (avAIlAbLE from GleN REseArch, sTErlinG, Va. aND CLontech, PAlo AltO, caLiF.). The samE mErcaptO aLkaNolS have BEen aTtacheD to contrOlled POre glass (CPG) to gIVe solid supporTS wHICh YIeld 3'-ThiOlated oligoNuclEOtidEs haVInG a pHOsphaTe or tHiOPhOSphate linkage betweeN tHe linkEr and The oligonucleOtide. In anoTHER approacH, oliGOnUCleotides havinG 5'-aminO linkers haVE been conVerteD into oliGonucleotIDEs having 5'-ThiOl lInkErs BY TrEatment with diTHIobiS-(N-SucciniMidYl)propiOnaTe oR N-sUccInImidyl-3-(2-pyrIdyldithIo)PrOpIoNatE follOWed by ditHiOthReItoL (DTT) (SEE, BischOff, et Al., AnAl. biOCheM. 1987, 164, 336 and GauR, Et AL., nucl. acIdS Res. 1989, 17, 4404). assElIne, et Al., TeTRahEdron 1992, 48, 1233 anD Fidanza, eT al., j. am. ChEm. soC. 1992, 114, 5509, have usEd either
 1987, 15, 4857 and biotin  in the sa me ma nne r a sdesc ribe d in PCT appli c atio n PCT/US/02198. Fluore scein ,b ioti n  a nd py rene we r ea l soli nk edin th e sam e m anner a s reported  by  T elser, et al . ,J. Am. Che m.Soc. 1989, 1 11,  6966.  A  co m merci alreage nt, Am i no-Mod ifier-dT,  f r om Gle n  Resear c h  C orpo ration (Sterling, Va . ) can be utili zed to  i n tr o d uce  py rimidine n uc leoti d es bear i ng s i mil a r linking gro ups into ol i gon ucleot id es. Sproat , etal . , N ucl. AcidsRes.  1987, 15 , 4837 ,  have s y nthesiz ed 5'- mer cap to n u cl eo sid es and in cor p ora ted them  i nt o oli gonu c l e o tide s.Seve ral p hosphoramidit esandH -ph ospho nates  hav ebeenreport ed fo rintroduction of  a 5 '-thiol l ink er  vi aa pho s phatelin kag e (see,  Mori,e t.al . , Nu cleosides and Nucl eo t i de s, 1989,  8, 64 9 ;WO 89/02931  ( Lev enso n ,  et a l.)p ub lished A pr. 6, 19 89 ; Sinha ,et al. ,Nuc l.Acids .  Res . 1988 , 16, 26 59).T he amidites pr o vide means fo r  a t t ac h ment  of  a HS--(CH. sub. 2 ).su b.n- -O --P ( .dbd. O)--O -l i nk a ge to the oligomer.  A lso, d isulf ide-protected  mercaptoa l k anols ha ve b e en used to yieldphosp horamidite s  (availa ble f rom Glen  Research , Sterling , V a.and  Cl o n te ch, Palo Alto , Cali f. ). Thesam e merca pto  al kan ols  h ave beenattached  t oco nt rol led p o re glass  ( CPG )togives olid s uppor ts w hi ch yie ld 3'-t h io l a tedol ig onuc leo ti des h avin g  aphospha te or thi oph o spha te  l inkagebetween the l in ker and th eoli gonucl e o tide. In  another approach, olig o nucleot ide s hav ing5'-aminolin kers h ave been c onvert ed in to  ol i g onucl e o ti des  h aving 5'-t h i ollinke rs  bytreatme nt with dithiobis- ( N-s uccinimidyl)p rop iona t e  o r N - su c cin im i dyl - 3 -(2-pyridyldith io)propion at e  f ollowed by dit hi othreit ol (DTT ) (Se e , Bisch off, et a l., Anal.  B ioch e m . 1 987, 164,336 andGaur, eta l., N u cl . Aci dsRes. 1 98 9,17, 4 404).A sse line,  et al .,  Tetra hedro n1992, 48 , 1233 and Fidanza, etal., J . Am.  Ch em. Soc.199 2 , 1 14, 5509,  hav e used eit her 
 1987,_15, 4857_and biotin in the_same manner_as_described in_PCT_application PCT/US/02198. Fluorescein,_biotin and pyrene_were also linked in_the same manner_as_reported by Telser, et al., J. Am. Chem. Soc. 1989, 111, 6966. A commercial_reagent,_Amino-Modifier-dT, from_Glen_Research_Corporation (Sterling, Va.) can be_utilized to introduce pyrimidine nucleotides_bearing similar_linking groups into oligonucleotides.
Sproat, et al., Nucl. Acids_Res._1987, 15, 4837,_have synthesized 5'-mercapto nucleosides and incorporated them into oligonucleotides._Several phosphoramidites and H-phosphonates have been_reported for introduction_of_a_5'-thiol linker via a_phosphate linkage (see, Mori, et. al.,_Nucleosides and Nucleotides, 1989, 8, 649;_WO 89/02931 (Levenson, et al.) published Apr._6, 1989; Sinha, et al., Nucl._Acids. Res. 1988, 16, 2659)._The amidites_provide means for attachment of_a HS--(CH.sub.2).sub.n --O--P(.dbd.O)--O-linkage_to the_oligomer. Also, disulfide-protected_mercapto alkanols have been used to_yield phosphoramidites (available_from Glen Research, Sterling, Va. and_Clontech,_Palo Alto, Calif.)._The_same_mercapto alkanols_have been attached_to_controlled pore_glass_(CPG) to give solid supports which_yield_3'-thiolated oligonucleotides having a phosphate or thiophosphate_linkage between the linker_and_the oligonucleotide. In another_approach, oligonucleotides having 5'-amino linkers_have been converted into oligonucleotides having_5'-thiol linkers_by treatment_with dithiobis-(N-succinimidyl)propionate or N-succinimidyl-3-(2-pyridyldithio)propionate followed by dithiothreitol (DTT) (See, Bischoff, et_al., Anal. Biochem. 1987, 164, 336_and Gaur, et al.,_Nucl. Acids_Res._1989, 17, 4404)._Asseline,_et al.,_Tetrahedron 1992, 48, 1233 and Fidanza, et_al., J._Am. Chem. Soc. 1992, 114, 5509,_have used either