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The Main Tea Eta Datelor Mai Al Matlamat Hartur THE MAIN TEA ETA USDATELOR 20180057525A1 MAI AL MATLAMAT HARTUR ( 19) United States (12 ) Patent Application Publication ( 10) Pub . No. : US 2018 / 0057525 A1 Simon et al. (43 ) Pub . Date : Mar . 1 , 2018 (54 ) SOLID PHASE PEPTIDE SYNTHESIS 2014 , which is a continuation - in - part of application PROCESSES AND ASSOCIATED SYSTEMS No. 13 /833 ,745 , filed on Mar . 15 , 2013, now Pat. No. 9 , 169, 287 . @(71 ) Applicant : Massachusetts Institute of Technology , Cambridge , MA (US ) Publication Classification (51 ) Int. CI. @(72 ) Inventors : Mark David Simon , Gainesville , FL CO7K 1 / 04 (2006 . 01 ) (US ) ; Bradley L . Pentelute , COZK 1 / 08 (2006 . 01 ) Cambridge , MA (US ) ; Andrea Adamo , CO7K 1 / 06 ( 2006 .01 ) Cambridge , MA (US ) ; Patrick Louis (52 ) U . S . CI. Heider , Midland , MI (US ) ; Klavs F . ??? .. .. .. C07K 1 /042 ( 2013 .01 ) ; COOK 1 /061 Jensen , Lexington , MA (US ) ( 2013. 01 ) ; CO7K 1/ 045 ( 2013 .01 ) ; C07K 1 / 08 (2013 .01 ) @( 73 ) Assignee : Massachusetts Institute of (57 ) ABSTRACT Technology , Cambridge , MA (US ) Systems and processes for performing solid phase peptide synthesis are generally described . Solid phase peptide syn (21 ) Appl. No. : 15 /602 , 056 thesis is a known process in which amino acid residues are added to peptides that have been immobilized on a solid May 22, 2017 support . In certain embodiments , the inventive systems and ( 22 ) Filed : methods can be used to perform solid phase peptide syn thesis quickly while maintaining high yields . Certain Related U . S . Application Data embodiments relate to processes and systems that may be (63 ) Continuation of application No . 14 / 776 , 870 , filed on used to heat, transport , and/ or mix reagents in ways that Sep . 15 , 2015 , now Pat. No . 9 ,695 , 214 , filed as reduce the amount of time required to perform solid phase application No . PCT/ US2014 /017970 on Feb . 24 , peptide synthesis . Patent Application Publication Mar: 1 , 2018 Sheet 1 of33 US 2018/ 0057525A1 ?] [ ] [? ] ? 30 - ???????35 ?????? |+ - 10 ?|-,??? — ? ???? ? _w B ???????????? FIG . 1 PatentPatent Application Pub Publication Mar. 1 , 2018 Sheet 2 of 33 US 2018 / 0057525 A1 50 % Piperidine MeOHDMF ) in DME . w . L WWWWYW . Coupling HPLCwwwwwwwww w Pumpwwwwwwwwwwwwww Solution Syringe Pump Column ( Chart Recorder) UV detector WO : . : . : . : . : Wasteh ohohohohohoto FIG . 2A FIG . 2B Fmoc - ALFALFA -CONH2 .* wwwwwwwwwwwwwwwwwwwsnerNordkorero 10 13 16 19 Time (min ) FIG . 2C Patent Application Publication Mar. 1 , 2018 Sheet 3 of 33 US 2018 / 0057525 A1 je FIG . 2D Patent Application Publication Mar. 1 , 2018 Sheet 4 of 33 US 2018 / 0057525 A1 S e * * . LYRAGCCNH 5*555 * * . *. * **** 14 *** *** . .- ** des Arg . * * * * * * * * * * * * * . .. .. .. .. .. .: : . * * . * * * * * * * * * * * ** ** * ** * * ** * * * ** * * * * * * * * ** ** * * ** * * * * * wwwwwwwwwwwwww suitsusimwambie in * ????6 ????7 ????8 ? 9???? ?? 10????? ???11 ???? ?? 12 ???13 ?? ????14 ????15 16???? OWL ) ur( FIG . 3A * * * * ** * * * * Fmoc - ALF- CONHA . * * * * * * * W * S . * * * . *** wiv * * . * * * * * * ." * * * * * * wwwwwwwwwwwwwwwww * . * ,*.5 * ** * * ** ** ^ . WWW 90 Sec . .. .. .. .. .. .. .. .. .. .. .. .. 15 16 17 18 au ) uruu( 19 FIG . 3B Synthetic timeline at 60 C Couple JOU OMF wash wwwwwwwwwwwwwwwww 60 120 180 240 300 seconds FIG . 3C Patent Application Publication Mar. 1 , 2018 Sheet 5 of 33 US 2018 / 0057525 A1 ACP (65 - 74 ) [M + 2H ]2 * VQAAIDYING .CONH2 531. 78 60°c60°C ,HATU , flow (M +* 4* )* * 1062 .56 des Val .. 400 ???? ?? ? ?? ? ?800 ????? ?? ?? ??? ?? ???? ?? ?? ?????????? 1200 ?? ???? ?? ? ???? ?? * * * * * * * * * * * * * * * * * www * www . www .www www. www . www 4 6 8 10 12 14 16 18 20 Time (min ) FIG . 4A (M + 2H |2 # (M +H1 * ACP (65 - 74 ) 531. 78 1062 56 VOAAIDYING -CONH , * 60°C , HBTU , flow . * * * . 400 . 800 .. ..1200 . * * * * * * * * * * * * * * * * * * * * * * * * * * w . .. wwwwww.. .. woon * * * * * * * * * * * * * * ** * * * * * * * * * * * * ** * * w 4 6 8 10 12 14 16 18 20 Time (min ) FIG . 4B Patent Application Publication Mar. 1 , 2018 Sheet 6 of 33 US 2018 / 0057525 A1 ACP (65 - 74 ) IM * 2H12 ING -CONH (M + 2H ]2 + VQAAIDYING -CONH Er, 531. 78 RT, HBIUHBTU , flow * [ M * HD* w des o 406206256 * * 166666666* 400* * * ** * ** 800 ** * * * * 1200* * * * * www he * * * * ** * * * one * * . .. 10 i2 wwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwww14 16 18 20 Time (min ) FIG . 4C ACP (65 - 74 ) [M + 2H ]2 * M *Hy * VQAAIDYING - CONH , 531. 78 1062 56 RT, HBTU , batch . des Q . * . "* . www w * * 400 800 1200 . .. * * * * * * ** * * * wwwwwwwwwwwww4 6 8 * ** 10 12 ** * * * * * ** * * * * * * * * 14 ** * * * * * * * * * ** * * * ** * * *16 * ** * * * ** * * * * ** * * * * * *18 * * ** * * * ** ** * * ** * 20 Time (min ) FIG . 4D Patent Application Publication Mar. 1 , 2018 Sheet 7 of 33 US 2018 / 0057525 A1 PnIA (A10L ) Conotoxin GCCSLPPCALNNPDYC - CONH , IM * 2H2* Obs . 1667 .66 Da M * * * Calc . 1667 65 Da * 1668 .66 * 600 1000 1400 1800 W13 a termeten 4 * * ** * 6* ** ** * * * * * * * * * * * * * * * * * 10 * ** * * 12 14 16 18 20 Time (min ) FIG . 5A HIV - 1 PR (81 - 99 ) PVNIIGRNLLTQIGCTLNF -CONH , 3 + (M + 2H |2 * IM + 3H )* * 1043. 59 www Obs . 2085 . 17 Da 696 .06 Calc . 2085 . 15 Da * * * * * * * * * * present* the 400 * * * ** .. .. .. .. * ** * * * Wiwi* ** * * * . * * * wwwwwwwwwwwww4 6 10 12 14 16 18 20 Time (min ) FIG . 5B Patent Application Publication Mar. 1 , 2018 Sheet 8 of 33 US 2018 /0057525 A1 FIG . 6A . FIG . 6B FFFFIG . 6C Patent Application Publication Mar. 1 , 2018 Sheet 9 of 33 US 2018 / 0057525 A1 FIG . 6D waumwona FIG . 6E Patent Application PublicationPublication Mar . 1 , 2018 Sheet 10 of 33 US 2018 /0057525 A1 ( 1 - 1271 ) - NH2 Cys - (28 - 397 -NH2 Cys. - 40- 58 ) 1 , 2 www NCLLO (1 - 39 -NH2 1, 21 INCL ( 1 - 58 ) FIG . 7A HNHNOO IM * 5H15 * 669. 94 (M + 4H74 * (1 - 27 www. 837 . 17 IM * 3413 + Obs - 3343. 68 Da 1115 . 90 Calc * 3343. 66 Da * * * * * * * * * * * * * * * * ** * * * * * * * * * * * * * * * * * * * * * * * * * ** * * * * * * * * * * * * * * * * ** * * * ** * * * * * * * 600 800 1000 **** * * * * * * * ** * * * ** * * * * * * * ** ** * ** * * ** * * ** ** * * ** * * * ** * * * * * * * ** ** ** ** www . .. .. .. .. .. .. .. .. .. 4 6 8 10 Time12 (min ) 14 16 18 20 FIG . 7B Patent Application Publication Mar . 1 , 2018 Sheet 11 of 33 US 2018 /0057525 A1 [M * 3H ]* * THZ- AFIQSLKDDPS -CONHNH , 450 .56 ( M + 2H12 * . 675 . 33 THz (28 - 39 N NH2 . (M + 1H11 * * * Obs - 1348. 64 Da . 1349 .65 Calo + 1348 .63 Da 400 800 1200 ** ** * .. .. .. w www 4 . 6 . 8 10 Time12 ( min ) 14 16 18 20 FIG . 70 4 + Cys -SANLLAEAKKLNDAQAPK - CONH , 497 . 02 * (M + 3H13 * Cys- (40 - 58 ) * 662 . 36 Obs 1983 .06 Da * * (M + 2H12 * Calc 1983 ,05 Da * 993 . 04 * * 400 800 . * * * * * * * * * * * * * * * * * * * * * * * * * 4 ** ** *6 ** * * * ** ** * * * *8 * ** * * * 10 12 14 16 18 20 . w ; Time (min ) FIG . 7D Patent Application Publication Mar . 1 , 2018 Sheet 12 of 33 US 2018 /0057525 A1 (M + 7H17 * 944 . 32 Obs * 6599 . 25 Da (M + 6H16 * Calc - 6599 .29 Da 1101. 55 . *11111111111 * (M * 5H15 + Deconvolutedolute 1321. 66 . 6603 .67 Da * * * . 800 1200 1600 5000 * * ** ** * * * ** * 8000* * * * WWWM . www 4 6 8 wwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwww10 12 14 16 18 20 Time (min ) FIG . 7E Patent Application Publication Mar . 1 , 2018 Sheet 13 of 33 US 2018 /0057525 A1 2013 Wood 8030NMWIBAWN0O3XNSXNOA -KNHMOO WOWO Singganganmugamugamugam Retention Time (min ) FIG . SA Manual Boc GGGGGVONXENXEQONAKYELMANLNEBORX Uomovou TO 280 Retention Time (min ) FIG . 8B Patent Application Publication Mar . 1 , 2018 Sheet 14 of 33 US 2018 /0057525 A1 Waunoto Witam www MYYYYYY MW Retention Time (win ) FIG . 8C Morat & The A6091KOOPSX NOUTOVOL inseriti internet bantuan the batterie per totalitat de la intentant tota la totalitat a la ciutat la a la planting to think that the title thing the title to thank that the station to host to the one10 thing 12 den14 consistorien is estimation important16 in initiationis situation this18 in is season this in is intimation tamaran Retentionle ) FIG . 8D Patent Application Publication Mar. 1 , 2018 Sheet 15 of 33 US 2018 /0057525 A1 How tom CSAN LABAKKUNOAQARK .COM WWW wwwwwwwwwwwwwwwwwwwwwwwwwwww Win TO 27 TTa ** * Rete ime (mm ) FIG . 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