Study yields more than a million new cyclic compounds, some with pharmaceutical potential

Date

03/12/18
Photo by Don Hamerman

Researchers say they can now produce a vast library of unique cyclic compounds, some with the capacity to interrupt specific protein-protein interactions that play a role in disease. The new compounds have cyclic structures that give them stability and enhance their ability to bind to their targets.  

The study, reported in the journal Nature Chemical Biology, also revealed that one of the newly generated compounds interferes with the binding of an HIV protein to a human protein, an interaction vital to the virus’s life cycle.

Most drug-discovery efforts focus on disease-inducing interactions in enzymes and proteins that involve classic “lock-and-key” mechanisms, said University of Illinois chemistry professor Wilfred van der Donk, a Howard Hughes Medical Institute Investigator who co-led the study with University of Southampton chemical biology professor Ali Tavassoli. “In most cases, small chemical drugs bind to cavities in enzymes, where the chemical reactions take place. By binding to these crevices, the drugs prevent the enzymes from working.”

However, many disease processes involve protein-protein interactions that do not fit this model, van der Donk said.

“These have long been considered challenging because they do not involve such cavities. These protein-protein interactions often are made up of extended surfaces that can be difficult to inhibit with small molecules,” he said.

Linear peptides also are problematic. They can be “floppy, like spaghetti, and therefore most of the time are in incorrect orientations to bind,” van der Donk said. Cyclic molecules composed of one or more rings of amino acids are more stable and less susceptible to cellular enzymes that tend to chew off the ends of linear peptides. They are thus more likely to successfully bind to their targets.

In the new study, van der Donk and his colleagues made use of an enzyme they discovered from a bacterium that lives in the ocean.

“This enzyme’s natural role is to make about 30 different cyclic proteins, and we tested whether it could make analogs of these natural products in Escherichia coli,” van der Donk said. E. coli has been used as a drug-producing factory for pharmaceutical products.

The genetic sequences inserted into E. coli all coded for a series of amino acids recognized by the enzyme. By randomly adding specific amino acids to this “leader sequence,” the team was able to generate a library of more than a million unique multicyclic proteins.

Tavassoli and his colleagues next screened this library in genetically engineered E. coli for proteins that could interrupt the binding of the HIV protein to its human host cell target.

“We engineered the genes of the E. coli strain such that its survival depended on disrupting the interaction between the human protein and an HIV protein,” Tavassoli said. His team found three potential therapeutic agents. Further testing revealed that one of the three worked best. In a test tube and in cells, the compound bound to the human protein, stopping the HIV protein from interacting with it.

This drug agent likely will not be used therapeutically, however, as it may have toxic side effects at high doses as a result of its interaction with the human protein, the researchers said.

“The real advance here is the ability to generate libraries of millions of potentially therapeutic agents,” Tavassoli said. “These could be screened to identify inhibitors of other disease-related processes, which is where its real potential lies.”

The National Institutes of Health, the Howard Hughes Medical Institute and the United Kingdom Engineering and Physical Sciences Research Council supported this research. Van der Donk also is an affiliate of the Carl R. Woese Institute for Genomic Biology at the U. of I.


Diana Yates, Life Sciences Editor, Illinois News Bureau

Related People

vddonk

Directory

scheelinAlexander
Scheeline
bjmccallBenjamin
McCall
cmartn10Calgary
Martin
r-gennisRobert
Gennis
j-gerltJohn
Gerlt
sgranickSteve
Granick
mgruebelMartin
Gruebele
hergenroPaul
Hergenrother
huangRaven
Huang
mlkraftMary
Kraft
leckbandDeborah
Leckband
yi-luYi
Lu
martinisSusan
Martinis
snairSatish
Nair
eoldfielEric
Oldfield
rienstraChad
Rienstra
cmsCharles
Schroeder
zanZaida
Luthey-Schulten
sksScott
Silverman
s-sligarStephen
Sligar
zhao5Huimin
Zhao
pbraunPaul
Braun
mdburkeMartin
Burke
jeffchanJefferson
Chan
sdenmarkScott
Denmark
dlottDana
Dlott
foutAlison
Fout
agewirthAndrew
Gewirth
ggirolamGregory
Girolami
sohirataSo
Hirata
jainPrashant
Jain
jkatzeneJohn
Katzenellenbogen
nmakriNancy
Makri
douglasmDouglas
Mitchell
jsmooreJeffrey
Moore
murphycjCatherine
Murphy
r-nuzzoRalph
Nuzzo
dimerPhilip
Phillips
rauchfuzThomas
Rauchfuss
joaquinrJoaquín
Rodríguez-López
sarlahDavid
Sarlah
kschweizKenneth
Schweizer
jsweedleJonathan
Sweedler
vddonkWilfred
van der Donk
renskeRenske
van der Veen
vuraweisJosh
Vura-Weis
mcwhite7M.
White
sczimmerSteven
Zimmerman
beakPeter
Beak
wklemperWalter
Klemperer
jdmcdonaJ.
McDonald
mvp11Michael
Pak
pogoreloTaras
Pogorelov
mshen233Mei
Shen
dewoonDavid
Woon
wboulangWilliam
Boulanger
rxbRohit
Bhargava
qchen20Qian
Chen
jianjuncJianjun
Cheng
hy66Hong
Yang
andinomaJosé
Andino Martinez
decosteDonald
DeCoste
thhuangTina
Huang
tjhummelThomas
Hummel
dkellDavid
Kell
doctorkMichael
Koerner
marvilleKelly
Marville
crrayChristian
Ray
tlbrownTheodore
Brown
rmcoatesRobert
Coates
thdjrThom
Dunning
dykstraClifford
Dykstra
j-jonasJiri
Jonas
j-lisyJames
Lisy
shapleyJohn
Shapley
pshapleyPatricia
Shapley
awieckowAndrzej
Wieckowski
zumdahl2Steven
Zumdahl
ksuslickKenneth
Suslick
jcoxJenny
Cox
staciryStaci
Clodfelder
sqdSean
Drummond
dmillsDouglas
Mills
sheeleySarah
Sheeley
jsmaddenJoseph
Madden
cknight4Connie
Knight
schulzeHeather
Schulze
slangleySamantha
McLain
ssmurrayStar
Murray
kbaumgarKeena
Finney
adkssnBeatrice
Adkisson
bmylerBeth
Myler
trabari1Katie
Trabaris
kewatsonKaren
Watson
strussTheresa
Struss
metclfKara
Metcalf
ljohnso2Lori
Johnson
jenruslJennifer
Russell
lchenoweLeslie
Chenoweth
jcfJonathan
Freiman
wdedoWolali
Dedo
spinnerDavid
Spinner
plblumPatricia
Simpson
stevens2Chad
Stevens
lsagekarLori
Sage-Karlson
bertholdDeborah
Berthold
kecarlsoKathryn
Carlson
sdesmondSerenity
Desmond
axelson2Jordan
Axelson
scbakerStephanie
Baker
pflotschPriscila
Falagan Lotsch
dgrayDanielle
Gray
thennes2Tom
Hennessey
mhettingMary Jo
Hettinger
holdaNancy
Holda
aibarrAlejandro
Ibarra
kimshSung Hoon
Kim
kocherg2Nikolai
Kocherginsky
philipk2Philip
Kocheril
legare2Stephanie
Legare
alewandoAgnieszka
Lewandowska
bdmccallBirgit
McCall
smccombiStuart
McCombie
jdm5Justin
McGlauchlen
egmooreEdwin
Moore
myerscouKathleen
Myerscough
snalla2Siva
Nalla
romanovaElena
Romanova
roubakhiStanislav
Rubakhin
shvedalxAlexander
Shved
asoudaAlexander
Soudakov
xywangXiying
Wang
kwilhelKaren
Wilhelmsen
wilkeyRandy
Wilkey
silongSilong
Zhang
schlembaMary
Schlembach
trimmellAshley
Trimmell
emccarr2Elise
McCarren
cmercierChristen
Mercier
atimpermAaron
Timperman
niesShuming
Nie
hshanHee-Sun
Han
mmgMutha
Gunasekera
kknightsKatriena
Knights
lisawLisa
Williamson
keinckKatie
Einck
kneef1Kaitlyn
Neef
park384Joyce
Park
jmadden4Jason
Madden
txiang4Tiange
Xiang
e-rogersElizabeth
Rogers
j-hummelJohn
Hummel
i-paulIain
Paul
munjanjaLloyd Tafara
Munjanja
glnGayle
Nelsen
agerardAnna
Gerard
powerskaKimberly
Powers
lolshansLisa
Olshansky
miricaLiviu
Mirica
qingcao2Qing
Cao