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ChineseBulletinofLifeSciences2210201010Vol.22,No.10Oct.,20101004-0374(2010)10-1053-162010-04-192010-04-23(30873136)*E-mailaihuanie@yahoo.comTel010-66931643(100850)------Q51;R97-4ARecentprogressintargetingprotein-proteininteractionsforsmall-moleculedrugsdiscoveryNIEAi-hua(InstituteofPharmacologyandToxicology,AcademyofMilitaryMedicalScience,Beijing100850,China)Abstract:Protein-proteininteractionsplayacrucialroleinnumerousvitalcellfunctions.Targetingprotein-proteininteractionsisoneofthemostimportantstrategiesofdrugdiscovery,butdiscoveringsmall-moleculedrugsthatdisruptprotein-proteininteractionsisanenormouschallenge.Howevermanysmallmoleculeswhichcanmodulatetheprotein-proteininteractionshavebeendiscoveredintherecentyears.Thisreviewwillfocusonsmall-moleculeinhibitorsofprotein-proteininteractionsinvirusentry,apoptosispathwayandneurodegenerativediseases.Keywords:protein-proteininteractions;smallmoleculedrug;inhibitorsDNA-(protein-proteininteractions,PPIs)375000-[1]PPIs---1--1500~3000Å2[2,3]1054--(hotspot)[4]ClacksonWellsX-(hGH)(hGHbp)[5,6]hGHhGHbp1350Å230ΔG=–12.3kcal/molhGH31885%hGHbpW104W169–4.5kcal/molhGHhGHbp(hotregion)---[7][8]-(PDB:1guy)6414[9]2---/--/(clefts/pockets)/[10]NMRX-PPIsQ-SiteFinder[11,12]/PPIs(PPIM)PPIs[13]-[14]PPIs[15]WellsMecleman[16]-300~1000Å2[17]600Å2PPIs2.1DNAmRNADNARNA1055--2.1.1(HIV)HIVT-CD4gp120gp120gp41gp41[18]CD4gp120gp120gp120CCR5CXCR4gp41N-()gp41(HR1HR2)[19]HIV-CD4370(D1~D4)D1gp120D1F43R59gp120(V1~V5)(C1~C5)V1~V4loopC1~C5gp120HIV-1CD4-gp120[20]22CD426gp120CD4F43gp120E370I371N425M426W427G473D368CD4-gp12023%gp120CD41~3811(BMS-378806)[21]2(BMS-488043)[22]Bristol-MyersSquibbgp120-CD4HIV-111gp120CD4(sCD4)gp120BMS-378806BMS-488043gp120CD4-F43[23-25]sCD4gp120CD4[26,27]BMS-378806IIIgp1201~240~500gp120Trp112Thr257Ser375Phe382Met426[28]BMS-488043II[29]-gp120HIV-1CCR5CXCR4[30]352N-Loop(ECL1~ECL3)(TM1~TM7)Loop(IL1~IL3)C-CXCR4T-(X4)HIVCCR5(M)-(X5)HIV()NMR[31-34]gp120V3loop(4-strandedbridgingsheet)CCR5CXCR4(ECL2)N-gp120CCR5[31,34]V3loopF322Y323T324T325G326CCR5CEL2I165F182P183Y184Y187F189W190gp120V3loopE327G326H315CCR5M1Q186Y14V3loopK312T324R333CCR5Y184M1S185CCR5N-Y10()D11Y15gp-120R327R440I439gp120CXCR4[35,36]gp120V3loopR298R303R306R318CXCR4N-E2Y7D10Y12E15D20Y21D22ECL2N176E179D182R183Y184D187R188F189Y190P191D193gp120CCR5CXCR4CCR53456[37]R5HIV-13(maravirocUK-1056427857)[38]PfizerCCR52007FDA4(AplavirocGSK-873140)[39]GlaxoSmith-KlineIIb5(VicrivirocSCH417690)[40]Schering-PloughIII6(TAK-220)[41]TakedaIICCR5CCR5(TM)(W86W94Y108F109T195I198W248Y251E283M287)[42]7(AMD3100)8(AMD070)AnorMEDCXCR4[37]X4HIV-1AMD3100CXCR4ECL2D182D193TM4D171TM6D262gp120CXCR4[43]AMD070CXCR4Y45(TM1)W94(TM2)D97(TM2)D171(TM4)D262(TM6)E288(TM7)AMD070CXCR4CXCR4CXCR4gp120[44]AMD3100IAMD070CXCR4HIV-1X4-II[45]9(KRH-3955)KurehaCXCR4[46]CXCR4(ECL~ECL3)X4HIV-1X4HIV-1HIV-1gp41345Igp41(512~683)(684~704)(705~856)(FP512~527)N-(HR1542~592)C-(HR2623~664)(TR665~683)(CCR5CXCR4)gp120gp41gp41HR1HR2[19]HR1(N36)HR2(C34)N36C34[47]N36L566T569V570I573K574Q577L565'L568'T569'W571'G572'I573'L576'C34I635D632W631W628N36C34()N36C34HR1HR210(NB-2)11(NB-64)[48]gp41HR1K57410W571I573L57611L565L568V570W571I573gp4112gp41[49]gp41L566L568V570W571K574HIV-1IIIB94UG103EC50100nmol·L-12.1.2(hRSV)(hRSV)hRSVhRSVFGSHSHGFF574INCFF0F2(1~130)(130~136)F1(137~574)FF1CF1N-191057FF1N-1/3α-HR1(l49~206)α-F1βFHR2(474~523)(gp41)F-HR1HR2[50]HR1HR2hRSVhRSV-N57hRSV-C45[51]gp41N57C45N57T198V192L193K196I199D200L188'K191'V192'D194'L195'Y198'C45F483F488I492N57C45()13[52](BMS-433771)Bristol-MyersSquibbRSVF-HR2F483F488HR1RSVABEC5020nmol·L-1RSV14(JNJ-2408068)15(TMC353121)Johnson&JohnsonRSV[53]13F-HR2F483F488HR1RSV[54]RSV1415RSVpM14t1/2153h15RSVAB[54]2.1.3(denguevirus)RNA(EMC)7(NS1NS2ANS2BNS3NS4ANS4BNS5)EMCEIIE40%EEEEprM-EEEE(1~394)[55,56]I(DI)N-II(DII)EII(DII)III(DIII)DIDIIDIDIIIDIDIIDIDIIIEEDIDIIN--b-D-(b-OG)(T280V130L198Q200A205I270S274Q271L277K47T48E49L135A50Y137)Eklb-klb-DIIIDI~DIIEEE105816PurdueNCIb-OG16[57]EC500.9μmol·L-1170b-OG[57]17Novartisb-OG[58]BHK21DENV-2EC5070nmol·L-117b-OGL198P53E49Q2712.1.4(influenzavirus)(HA)(NA)(M2)M2NAM2NA[59,60]HA550HA1HA2HAHA2(176~221)N-()pHHA2[61]HA2L55V55R54E57HA2E97L98Y94L99A101(tert-butylhydroquinone,TBHQ)pH()HA2[62]pH18[63]H3N2MDCK(Madin-Darbycaninekidney)EC503~23μmoll·L-1H1N1H5N1H7N2BTBHQHA22.2-(programmedcelldeathapoptosis)-Bcl-2(IAPs)Caspasesp53MDM2-2.2.1Bcl-2Bcl-2cSmac/DIABLOEndoGOmin/HtrA2Bcl-2BakBokBaxBcl-XsBadBidBimBikHrkBnip3NixPumaBmfNoxaBcl-2Bcl-XLBcl-wAl/Bfl-1BooMcl-1BH1BH2BH3Bak()BaxBakBaxNMRBcl-XLBak72~87[64]Bcl-XLF97R100Y101A104F105L108V126L129F130I139V141A142F146Y195BakV74R76Q77L78A79I80I81D83D84I85N86()BH31059(Bcl-XLBcl-2,Bcl-wMcl-1)BH319(ABT-737)AbbottBcl-2Bcl-2(Ki1nmol·L-1)Bcl-XL(Ki0.5nmol·L-1)Bcl-w(Ki=0.9nmol·L-1)Mcl-1A1/Bfl-1Ki1μmol·L-1Bcl-2Bcl-XLABT-737[65]Bcl-XLBcl-XLF97A104F105L108V126L130V141A142F146Y197NSCLCABT-737H146H1963SCLCABT-73720(ABT-263)AbbottABT-737Bcl-2[66]Bcl-2(Ki1nmol·L-1)Bcl-XL(Ki0.5nmol·L-1)Bcl-w(Ki1nmol·L-1)Mcl-1(Ki=550nmol·L-1)ABT-737(SCLC)B-I[67]21(ObatoclaxGX15-070)GeminXBH3[68]Bcl-2(IC50=1.1μmol·L-1)Bcl-XL(IC50=μm