o-Pellx Mlmeucs 1haL ulsrupL

roLeln-roLeln lnLeracuons
Corey !ensen
Croup Meeung 4-12-12
o-hellx mlmeucs
1

AppoxlmaLely 40 of all proLeln secondary
sLrucLures are o-hellces
o-Pellces are Lyplcally 10 resldues long or
more and normally conLaln aL leasL 3 Lurns.
lnLeracung resldues occupy mosLly Lhe !" ! + 3,
! + 4, & ! + 7 posluons
Log values
Log(C
ocLonol
/C
waLer
)
Plgher Log = less hydrophlllc
o-Pellx Mlmeucs
1

1,1,6-LrlsubsuLuLed lndanes
2

1,1-posluons mlmlc !-1, !
osluon 6 mlmlcs !+1
neuropepude mlmlc Lo blnd Lo neuoropepude
recepLors (nk1-3)
Pad some selecuvlLy (e.g. nk1>nk3)
Showed proof of concepL
no mlmeuc showed greaLer amnlLy Lhan Lhe
naLural proLeln
o-Pellx Mlmeucs
1

1erphenyl
3

ueveloped by PamllLon and co-workers

Molecular modellng and crysLal sLrucLures show subsuLuuons aL Lhe !" ! + 3
or ! + 4, & ! + 7
1emplaLe occuples Lhe same space as Lhe o-hellx backbone
Mlmlcked Lhe o-hellx of Lhe enzyme smMLCk whlch blnds Lo Lhe proLeln
CaM
CaM blnds Lo an enzyme phosphodlesLerase (uL) aL Lhe same reglon as
smMLCk
Addluon of Lhe o-hellx mlmlc lnhlblLed Lhe CaM blndlng wlLh uL wlLh an
lC
30
of 800 nM.
lsomers were less poLenL
unsubsuLuLed Lerphenyl derlvauves had weak blndlng
1erphenyl Advances
roblem: oor waLer solublllLy and long
synLheuc rouLes
Soluuon: PeLerocycllc rlng
1rlsubsuLuLed Lerphenyl log = 7.4 replace
wlLh pyrldlng = 3.4
yrldazlne-based scaolds (d) showed less
poLency agalnsL 8cl-x
L
/8ak proLeln-proLeln
lnLeracuon Lhan slmllar subsuLuLed Lerphenyl
analogue.
4

o-Pellx Mlmeucs
1

1,4-dlplperazlne benzene scaold
konlg deslgned
Allows sLereochemlsLry conLrol ln order Lo
probe acuve slLe (e)
o-Pellx Mlmeucs
1

3-6-3 lmldazole-phenyl-Lhlazole
scaold
SLrucLure (f)
ueslgned by PamllLon
Pas Leraryl core
3 membered rlng aromauc heLerocycles. More
waLer soluble and easler Lo synLheslze
Log (o/w) LrlmeLhyl-subsuLuLed Lerphenyl
analogue 7.3 compared Lo 2.3 model compound
ulsrupLed a Cdc42/ubs proLeln-proLeln
lnLeracuon wlLh (lC
30
=67.0 M)
3
o-Pellx Mlmeucs
1

1erephLhalamlde scaolds
6

8ely on lnLramolecular hydrogen bondlng
8esLrlcLs roLauon
Log (o/w) LrlmeLhyl-subsuLuLed Lerphenyl
analogue ls 7.3 and an all meLhyl subsuLuLed
LerephLhalamlde 4.4
lnhlbluon of 8cl-x
L
/8ak proLeln proLeln lnLeracuon
wlLh $
!
= .78 + 0.07 M buL Lerephenyl analogue had
$
!
= 0.114 M.
o-Pellx Mlmeucs
1

Cllgoamlde foldamer & ollgopyrldlne
carboxamldes
SLrucLure (l)
lncreased waLer solublllLy and easler Lo
synLheslze
Pave been shown Lo lnhlblL proLeln proLeln
lnLeracuons
o-Pellx Mlmeucs
1

8enzoylurea uerlvauves
Aromauc rlng lsosLere
Pydrogen bond lnLeracuons malnLaln a more
rlgld conformauon
Lasler Lo synLheslze and lower log value
Lhan Lerphenyl
8enzoylurea lsosLere of a poLenL Lerphenyl
showed less poLency agalnsL 8cl-x
L
/8ak
proLeln proLeln lnLeracuons ($!=2.4M vs.
$!=114nM)
o-Pellx Mlmeucs
1

8eferences
1. Cummlngs, C. C., PamllLon, A. u., !"#$%&'() &$(+,")-&$(+,") ")+,$./'()# 0"+1 )()-&,&'2"/3 #4.55 4(5,/%5, 6-1,5"7 4"4,'/#
2. u.C. Porwell, W. Powson, C.S. 8aLclle, P.M.C. Wlllems. 81, 2,#"9) (: 2"&,&'2, 1,5"/.5 4"4,'/#; +1, #<)+1,#"#3 +./1<=")")
$,/,&+($ .>)"+< .)2 /():($4.'().5 .).5<#"# (: ?3?3@-+$"#%A#'+%+,2 ")2.),#B %!&&'( )*+ ,-*., 4 (1996), pp. 33-42
3. Crner 8, LrnsL !1, PamllLon Au: 8(0.$2 &$(+,(4"4,'/#; +,$&1,)<5 2,$"C.'C,# .# #+$%/+%$.5 .)2 :%)/'().5 4"4"/# (:
,7+,)2,2 $,9"()# (: .) 6-D,5"7B / 0. ,-*. 1&2 3445" !"#67893:7898
4. S.M. 8lros, L. Molsan, L. Mann, A. Carella, u. Zhal, !.C. 8eed, !. 8ebek !r. D,+,$(/</5"/ 6-1,5"7 4"4,'/# :($ +.$9,')9 &$(+,")E
&$(+,") ")+,$./'()#B %!&&'( )*+ ,-*. ;*<, 17 (2007), pp. 4641-4643.
3. C.C. Cummlngs, n.1. 8oss, W.. kau, A.u. PamllLon. F<)+1,#"# .)2 A"(5(9"/.5 ,C.5%.'() (: . G-@-G "4"2.H(5,-&1,)<5-+1".H(5,
A.#,2 6-1,5"7 4"4,'/B ='( ;*<, 11 (2009), pp. 23-28
6. P. ?ln, C. Lee, k.A. Sedey, !.M. 8odrlguez, P. Wang, S.M. Sebu, A.u. PamllLon, 8,$,&1+1.5.4"2, 2,$"C.'C,# .# 4"4,'/# (:
1,5"/.5 &,&'2,#; 2"#$%&'() (: +1, I/5-7
J
KI.= ")+,$./'()B > 0. ,-*. 1&2, 127 (2003), pp. 3463-3468