摘要
人类T细胞白血病病毒Ⅰ型(HTLV-Ⅰ)的感染可以导致成人T细胞白血病(ATI)和热带痉挛性下肢瘫痪/HTLV-Ⅰ相关脊髓病(TSP/HAM)等其他慢性疾病,目前全世界范围内有2-3千万人为病毒携带者。HTLV-Ⅰ蛋白酶与这一病毒的复制密切相关,抑制蛋白酶的活性能够有效地阻止病毒的复制。因此,HTLV-Ⅰ蛋白酶是一个非常重要的抗HTLV-Ⅰ感染的研究靶点。
天然肽分子易于被体内的酶降解而失去活性,本文设计将含有羟甲羰基(HMC)结构的(2S,3S)-3-氨基-2-羟基-4-苯基丁酸(Apns)作为非天然氨基酸残基,引入底物的结构中,模拟天然底物被蛋白酶水解的过渡态类似物,从而阻断天然底物与酶的结合,有效抑制HTLV-Ⅰ蛋白酶活性。以KNI-10455(IC_(50)=140nM)作为先导化合物,在C端和N端引入不同的取代胺基和取代羧基,并逐步减小分子结构,通过液相合成的方法制备了66个未见文献报道的拟肽类化合物,其中53个为四肽化合物,9个为三肽化合物,4个为二肽化合物。新化合物的结构经核磁共振氢谱和质谱检测确证。
采用蛋白酶抑制剂活性测定方法对新化合物进行了初步抗HTLV-Ⅰ和HIV-1蛋白酶活性筛选。结果显示53个四肽化合物在50nM浓度下显示了较高的HIV-1蛋白酶抑制率(＞97%);42个四肽抑制剂具有高于先导化合物的抗HTLV-Ⅰ蛋白酶活性(IC_(50)＜137nM);二肽和三肽化合物在600nM浓度下对HTLV-Ⅰ蛋白酶没有显著的抑制作用(＜14%);其中活性最强的化合物是(R)-N-(2,2-二甲基)丙基-3-{{(2S,3S)-3-{(2S-2-[(2S)-2-丁酰胺基-2-苯基]乙酰胺基-3,3-二甲基}丁酰胺基-2-羟基-4-苯基}}丁酰基-5,5-二甲基-1,3-噻唑-4-甲酰胺(IC_(50)=74 nM)。
A large number of diseases including adult T-cell leukemia(ATL) and tropical spastic paraparesis/HTLV-I-associated myelopathy(TSP/HAM) are caused by the human T-cell leukemia virus typeⅠ(HTLV-I).HTLV-I infection is currently considered as an intractable disease because 20-30 million individuals worldwide are viral carriers.HTLV-I protease is responsible for the proliferation of the retrovirus and then becomes an attractive target for developing inhibitors against HTLV-I infections.
Substrates containing natural amino acid residues are easily digested by proteases. When a non-natural amino acid,(2S,3S)-3-amino-2-hydroxy-4-phenylbutyric acid(Apns), containing a hydroxymethylcarbonyl(HMC) isostere,that can mimic the tetrahedral transition-state of amino bond hydrolysis but cannot itself be hydrolyzed by the enzyme,is introduced,the protease's pharmacological actions are suspended.Using KNI-10455 as a reference compound(IC_(50)=140 nM),we were interested in modifying the N-and C-terminals and truncation studies to enhance HTLV-I protease inhibition.Sixty-six peptidic compounds containing Apns were prepared by solution phase peptide synthesis.Fifty-three of them were tetrapeptidic inhibitors.Nine of them were tripeptidic compounds.Four of them were dipeptidic inhibitors.The structures were identified by ~1H-NMR and MS spectra.
All novel compounds were evaluated for HTLV-I and HIV-1 protease assays. Fifty-three tetrapeptides exhibited high HIV-1 protease inhibition at 50nM(＞97%).Forty-two tetrapeptides showed potent HTLV-I protease activity(IC_(50)＜137nM) that were greater than the reference compound.None of the tri-and di-peptides efficiently inhibited HTLV-I protease at 600 nM(＜14%).The most potent HTLV-I protease inhibitor was(R)-N-(2,2-dimethyl) propyl-3-{{(2S,3S)-3-{(2S)-2-[(2S)-2-butyrylamino-2-phenyl]acetylamino-3,3-dimethyl}butan oylamino-2-hydroxy-4-phenyl}}butanoyl-5,5-dimethyl-l,3-thiazolidine-4-carboxamide(IC_(50)= 74nM).
引文
[1]Poiesz,B.J.;Ruscetti,F.W.;Gazdar,A.F.;Bunn,P.A.;Minna,J.D.;Gallo,R.C.Detection and Isolation of Type C Retrovirus Particles from Fresh and Cultured Lymphocytes of a Patient with Cutaneous T-cell Lymphoma.Proc.Natl.Acad.Sci.USA 1980,77(12),7415-7419.
[2]Yoshida,M.;Miyoshi,I.;Hinuma,Y.Isolation and Characterization of Retrovirus from Cell Lines of Human Adult T-cell Leukemia and its Implication in the Disease.Proc.Natl.Acad.Sci.USA 1982,79(12),2031-2035.
[3]Shuh,M.;Beilke,M.The Human T-Cell Leukemia Virus Type 1(HTLV-1):New Insight into the Clinical Aspects and Molecular Pathogenesis of Adult T-Cell Leukemia/Lymphoma(ATLL)and Tropical Spastic Paraparesis / HTLV-Associated Myelopathy(TSP/HAM).Microsc.Res.Techniq.2005,68,176-196.
[4]Bagossi,P.;Sperka,T.;Feher,A.;Kadas,J.;Zahuczky,G;Miklossy,G;Boross,P.;Tozser,J.Amino Acid Preferences for a Critical Substrate Binding Subsite of Retroviral Proteases in Type 1 Cleavage Sites.J.Virol.2005,79(7),4213-4218.
[5]Shuker,S.B.;Mariani,V.L.;Herger,B.E.;Dennison,K.J.Understanding HTLV-1 Protease.Chem.Biol.2003,10,373-380.
[6]Uchiyama,T.;Yodoi,J.;Sagawa,K.;Takatsuki,K.;Uchino,H.Adult T-cell Leukemia:Clinical and Hematologic Features of 16 Cases.Blood 1977,50(3),481-492.
[7]Takatsuki,K.Discovery of Adult T-cell Leukemia.Retrovirology 2005,2,16.
[8]Semmes,O.J.Adult T Cell Leukemia:A Tale of Two T Cells.J.Clin.Invest.2006,116(4),858-860.
[9]Uchiyama,T.Human T Cell Leukemia Virus Type 1(HTLV 1)and Human Diseases.Annu.Rev.Immunol.1997,15,15-37.
[10]Makino,M.;Shimokubo,S.;Wakamatsu,S.;Izumo,S.;Baba,M.The Role of Human T-Lymphotropic Virus Type 1(HTLV-1l)-Infected Dendritic Cells in the Development of HTLV-1-Associated Myelopathy/Tropical Spastic Paraparesis.J.Virol.1999,73(6),4575-4578.
[11]Miura,T.;Fukunaga,T.;Igarashi,T;Yamashita,M.;Ido,E.;Funahashi,S.;Ishida,T.;Washio,K.;Ueda,S.;Hashimoyo,K.;Yoshida,M.;Osame,M.;Singhal,B.S.;Zaninovic,V;Cartier,L.;Sonoda,S.;Tajima,K.;Ina,Y;Gojobori,T;Hayami,M.Phylogenatic Subtypes of Huamn T-lymphoyropic Virus Type Ⅰ and their Relations to the Anthropological Background.Proc.Natl.Acad.Sci.USA 1994,91,1124-1127.
[12]Proietti,F.A.;Carneiro-Proietti,A.B.F.;Catalan-Soares,B.C;Murphy,E.L.Global Epidemiology of HTLV-1 Infection and Associated Diseases.Oncogene 2005,24,6058-6068.
[13]Chen,Y A.,Lin,H.,Chou,P.A Population-based Epidemiological Study of Human T-cell Leukemia Virus Type 1 Infection in Kin-hu,Kinmen.Int.J.Cancer 1996,65,569-573.
[14]Mahieux,R.;Ibrahim,F.;Mauclere,P.;Herve,V;Michel,P.;Tekaia,F.;Chappey,C;Grain,B.;Ryst,E.V.D.;Guillemain,B.;Ledru,E.;Aporte,E.;The,G.D.;Gessain,A.Molecular Epidemiology of 58 New African Human T-Cell Leukemia Virus Type 1(HTLV-1)Strains:Identification of a New and Distinct HTLV-1 Molecular Subtype in Central Africa and in Pygmies.J.Virol.1997,71(2),1317-1333.
[15]Cassar,O.;Capuano,C;Meertens,L.;Chungue,E.;Gessain,A.Human T-cell Leukemia Virus Type 1 Molecular Variants,Vanuatu,Melanesia.Emerg.Infect.Dis.2005,11(5),706-710.
[16]Gastaldello,R.;Otsuki,K.;Barbas,M.G;Vicente,A.C.P.;Gallego,S.Molecular Evidence of HTLV-1 Intrafamilial Transmission in a Non-Endemic Area in Argentina.J.Med.Virol.2005,76,386-390.
[17]Yamaguchi,K.Human T-lymphotropic Virus Type I in Japan.Lancet 1994,343,213-216.
[18]Arisawa,K.;Soda,M.;Endo,S.;Kurokawa,K.;Katamine,S.;Shimokawa,I.;Koba,T;Takahashi,T.;Saito,H.;Doi,H.;Shirahama,S.Evaluation of Adult T-cell Leukemia/lymphoma Incidence and its Impact on Non-hodgkin Lymphoma Incidence in Southwestern Japan.Int.J.Cancer 2000,85,319-324.
[19]Matsuoka,M;Jeang,K.Human T-cell Leukemia Virus Type 1(HTLV-1)Infectivity and Cellular Transformation.Nat.Rev.Cancer 2007,7,270-280.
[20]Nicot,C.Current View in HTLV-1-Associated Adult T-Cell Leukemia/Lymphoma.Am.J.Hematol.2005,78,232-239.
[21]Nitta,T.;Kanai,M.;Sugihara,E.;Tanaka,M.;Sun,B.;Nagasawa,T;Sonoda,S.;Saya,H.;Miwa,M.Centrosome Amplification in Adult T-cell Leukemia and Human T-cell Leukemia Virus Type 1 Tax-induced Human T Cell.Cancer Soc.2006,97,836-841.
[22]O'Connor,S.;Taylor,C.E.;Hughes,J.M.Emerging Infection Determinants of Chronic Diseases.Emerg.Infect.Dis.2006,12(7),1051-1057.
[23]Delamarre,L.;Rosenberg,A.R.;Pique,C;Pham,D.;Dokhelar,M.A Novel Human T-Leukemia Virus Type 1 Cell-to-Cell Transmission Assay Permits Definition of SU Glycoprotein Amino Acids Important for Infectivity.J.Virol.1997,71(1),259-266.
[24]Igakura,T.;Stinchcombe,J.C;Goon,P.K.;Taylor,G.P.;Weber,J.N.;Griffiths,G M.;Tanaka,Y.;Osame,M.;Bangham,C.R.M.Spread of HTLV-1 Between Lymphocytes by Virus-Induces Polarization of the Cytoskeleton.Science 2003,299,1713-1716.
[25]Arisawa,K.;Soda,M.;Akahoshi,M.;Fujiwara,S.;Uemura,H.;Hiyoshi,M.;Takeda,H.;Kashino,W.;Suyama,A.Human T-cell Lymphotropic Virus Type-1 Infection and Risk of Cancer:15.4 Year Longitudinal Study among Atomic Bomb Survivors in Nagasaki,Japan.Cancer Sci.2006,97,535-539.
[26]Seydel,J.;Kramer,A.Transmission and Population Dynamice of HTLV-1 Infection.Int.J.Cancer 1996,66,197-200.
[27]Yamada,Y.;Tomonaga,M.;Fukuda,H.;Hanada,S.;Utsunomiya,A.;Tara,M.;Sano,M.;Ikeda,S.;Takatsuki,K.;Kozuru,M.;Araki,K.;Kawano,F.;Niimi,M.;Tobinai,K.;Hotta,T;Shimoyama M.A New G-CSF-supported Combination Chemotherapy,LSG15,for Adult T-cell Leukemia-lymphoma:Japan Clinical Oncology Group Study 9303.Br.J.Haematol.2001,113,375-382.
[28]Bazarbachi,A.;Nasr,R.;El-Sabban,M.;Mahe,A.;Mahieux,R.;Gessain,A.;Darwiche,N.;Dbaibo,G.;Kersual,J.;Zermati,Y;Dianoux,L.;Chelbi-Alix,M.;The,H.;Hermine,O.Evidence against a Direct Cytotoxic Effect of Alpha Interferon and Zidovudine in HTLV-1 Associated Adult T Cell Leukemia/lymphoma.Leukemia 2000,14,716-721.
[29]Ravandi,F.;Kantarjian,H.;Jones,D.;Dearden,C;Keating,M.;O'Brien,S.Mature T-cell Leukemias.Cancer 2005,104,1808-1818.
[30]Morrow,C.D.;Park,J.;Wakefield,J.K.Viral Gene Products and Replication of the Human Immunodeficiency Virus Type 1.Am.J.Physiol-Cell.Ph.1994,266,C1135-C1156.
[31]Grigorov,B.;Muriaux,D.;Argirova,R.;Darlix,J.-L.New Insight into Human Immunodeficiency Virus type 1 Replication.Biotechnol.Biotec.Eq.2005,19(1),3-15.
[32]Coffin,J.M.;Hughes,S.H.;Varmus,H.E.Retroviruses.ISBN 0-87969-497-1.Cold Spring Harbor Laboratory Press.1997.
[33]Kobayashi,M.;Ohi,Y.;Asano,T.;Hayakawa,T.;Kato,K.;Kakinuma,A.;Hatanaka,M.Purification and Characterization of Human T-cell Leukemia Virus Type I Protease Produced in Escherichia Coli.FEBS Lett.1991,293,106-110.
[34]Johnson,J.M.;Harrod,R.;Franchini,G.Molecular Biology and Pathogenesis of the Human T-cell Leukemia/lymphotropic Virus Type-1(HTLV-1).Int.J.Exp.Path.2001,82,135-147.
[35]Agbuya,P.G.;Sherman,N.E.;Moen,L.K.Proteolytic Processing of the Human T-cell Lymphotropic Virus 1 Reverse Transcriptase:Identification of the N-terminal Cleavage Site by Mass Spectrometry.Arch.Biochem.Biophys.2001,392,93-102.
[36]Mariani,V.L.;Shuker,S.B.Identification of the RT-RH/IN Cleavage Site of HTLV-1.Biochem.Biophys.Res.Commun.2003,300,268-270.
[37]Dash,C;Kulkarni,A.;Dunn,B.;Rao,M.Aspartic Peptidase Inhibitors:Implication in Drug Development.Crit.Rev.Biochem.Mol 2003,38(2),89-119.
[38]Ding,Y.S.;Owen,S.M.;Lai,R.B.;Ikeda,R.A.Efficient Expression and Rapid Purification of Human T-Cell Leukemia Virus Type 1 Protease.J.Virol.1998,72(4),3383-3386.
[39]Li,M.;Laco,G.S.;Jaskolski,M;Rozycki,J.;Alexandratos,J.;Wlodawer,A.;Gustchina,A.Crystal Structure of Human T Cell Leukemia Virus Protease,A Novel Target for Anticancer Drug Design.Proc.Natl.Acad.Sci.USA.2005,102,18332-18337.
[40]Kadas,J.;Weber,I.T.;Bagossi,P.;Miklossy,G;Boross,P.Narrow Substrate Specificity and Sensitivity toward Ligand-binding Site Mutations of Human T-cell Leukemia Virus Type 1 Protease.J.Bio.Chem.2004,279,27148-27157.
[41]Herger,B.E.;Mariani,V.L.;Dennison,K.J.;Shuker,S.B.The 10 C-terminal Residues of HTLV-I Protease are not Necessary for Enzymatic Activity.Biochem.Bioph.Res.Co.2004,320(4),1306-1308.
[42]Kobayashi,M.;Ohi,Y.;Asano,T.;Hayakawa,T.;Kato,K.;Kakinuma,A.;Hatanaka,M.Purification and Characterization of Human T-cell Leukamia Virus Type I Protease Produced in Escherichia Coli.FEBS Lett.1991,293,106-110.
[43]Louis,J.M.;Oroszlan,S.;Tozser,J.Stabilization from Autoprteolysis and Kinetic Characterization of the Human T-cell Leukemia Virus Type 1 Protease.J.Bio.Chem.1999,274,6660-6666.
[44]Tozser,J.;Zahuczky,G;Bagossi,P.;Louis,J.M.;Copeland,T.D.;Oroszlan,S.;Harrison,R.W.;Weber,I.T.Comparison of the Substrate Specificity of The Human T-cell Leukemia Virus and Human Immunodeficiency Virus Proteinases.Eur.J.Biochem.2000,267,6287-6295.
[45]Bagossi,P.;Sperka,T.;Feher,A.;Kadas,J.;Zahuczky,G;Miklossy,G;Boross,P.;Toszer,J.Amino Acid Perences for a Critical Substrate Binding Subsite of Retroviral Protease in Type 1 Cleavage Sites.J.Virol.2005,79,4213-4218.
[46]Maegawa,H.;Kimura,T.;Arii,Y.;Matsui,Y;Kasai,S.;Hayashi,Y;Kiso,Y Identification of Peptidomimetic HTLV-1 Protease Inhibitors Containing Hydroxymethylcarbonyl(HMC)Isostere as the Transition-state Mimic.Bioorg.Med.Chem.Lett.2004,14,5925-5929.
[47]Ding,Y S.;Rich,D.H.;Ikeda,R.A.Substrates and Inhibitors of Human T-cell Leukemia Virus Type 1 Protease.Biochemistry 1998,37,17514-17518.
[48]Naka,H.;Teruya,K.;Bang,J.K.;Aimoto,S.;Tatsumi,T.;Konno,H.;Nosaka,K.;Akaji,K.Evaluation of Substrate Specificity and Inhibition at PR/p3 Cleavage Site of HTLV-1 Protease.Bioorg.Med.Chem.Lett.2006,16(14),3761-3764.
[49]Daenke,S.;Schramm,H.J.;Bangham,C.R.M.Analysis of Substrate Cleavage by Recombinant Protease of Human of T cell Leukemia Virus Type 1 Reveals Preferences and Specificity of Binding.J.Gen.Virol.1994,75,2233-2239.
[50]Seiki,M.;Hattori,S.;Hirayama,Y;Yoshida,M.Human Adult T-cell Leukemia Virus:Complete Nucleotide Sequence of the Provirus Genome Intergrated in Leukemia Cell DNA.Proc.Natl.Acad.Sci.USA 1983,80,3618-3622.
[51]Clark,S.C.;Arya,S.K.;Wong-staal,F.;Matsumoto-kobayashi,M.;Kay,R.M.;Kaufman,R.J.;Brown,E.L.;Shoemaker,C.;Copeland,T.;Oroszlan,S.;Smith,K.;Sarngadharan,M.G.;Linder,S.G.;Gallo,R.C.Human T-cell Growth Factor:Partial Amino Acid Sequence,cDNA Cloning,and Organization and Expression in Normal and Leukemia Cell.Proc.Natl.Acad.Sci.USA 1984,81,2543-2547.
[52]Gallo,R.T.History of the Discovery of the First Human Retroviruses:HTLV-1 and HTLV-2.Oncogene 2005,24,5926-5930.
[53]Brik,A.;Wong,C.HIV-1 Protease:Mechanism and Drug Discovery.Org.Biomol.Chem.2003,1,5-14.
[54]Habeck,M.Spying on Nature's Drug Factories.Drug Discov.Today 2002,7(22),1109-1110.
[55]Minakakis-Moutevelis,P.;Gianni,M;Stougiannou,H.;Zoumpoulakis,P.;Zoga,A.;Vlahakos,A.D.;Iliodromitis,E.;Mavromoustakos,T.Design and Synthesis of Novel Antihypertensive Drugs.Bioorg.Med.Chem.Lett.2003,13,1737-1740.
[56]Nguyen,J.-T.;Yamani,A.;Kiso,Y.Views on Amyloid Hypothesis and Secretase Inhibitors for Treating Alzheimer's Disease:Progress and Problems.Curr.Pharmaceut.Des.2006,12,4295-4312.
[57]Abdel-Rahman,H.M.;Kimura,T.;Hidaka,K.;Kiso,A.;Nezami,A.;Freire,E.;Hayashi,Y;Kiso,Y Design of Inhibitors against HIV,HTLV-1,and Plasmodium Falciparum Aspartic Proteases.Bio.Chem.2004,385,1035-1039.
[58]Suguna,K.;Padlan,E.A.;Smith,C.W.;Carlson,W.D.;Davies,D.R.Binding of a Reduced Peptide Inhibitor to the Aspartic Proteinase from Rhizopue Chinensis:Implications for a Mechanism of Action.Proc.Natl.Acad.Sci.USA 1987,84,7009-7013.
[59]Swain,A.L.;Miller,M.M.;Green,J.;Rich,D.H.;Schneider,J.;Kent,S.B.H.;Wlodawer,A.X-Ray Crystallographic Structure of a Complex Between a Synthetic Protease of Human Immuodeficiency Virus and a Substrate-Based Hydroxylamine Inhibitor.Proc.Natl.Acad.Sci.USA 1990,87,8805-8809.
[60]Leung,D.;Abbenante,G;Fairlie,D.P.Protease Inhibitors:Current Status and Future Prospect.J.Med.Chem.2000,43(3),305-341.
[61]Eder,J.;Hommel,U.;Cumin,F.;Martoglio,B.;Gerhartz,B.Aspartic Protease in Drug Discovery.Curr.Pharm.Design 2007,13,271-285.
[62]Teruya,K.;Kawakami,T.;Akaji,K.;Aimoto,S.Total Synthesis of[L40I,C90A,C109A]-human T-cell Leukemia Virus Type 1 Protease.Tetrahedron Lett.2002,43,1487-1490.
[63]Akaji,K.;Teruya,K.;Aimoto,S.Solid-Phase Synthesis of HTLV-1 Protease Inhibitors Containing Hydroxyethylamine Dipeptide Isostere.J.Org.Chem.2003,68,4755-4763.
[64]Bang,J.K.;Naka,H.;Teruya,K.;Aimoto,S.;Konno,H.;Nosaka,K.;Tatsumi,T.;Akaji,K.Solid-Phase Syntheses of Olefin-Containing Inhibitors for HTLV-1 Protease Using the Horner-Emmons Reaction.J.Org.Chem.2005,70,10596-10599.
[65]Ami,E.;Nakahara,K.;Sato,A.;Nguyen,J.-T.;Hidaka,K.;Hamada,Y;Nakatani,S.;Kimura,T.;Hayashi,Y;Kiso,Y Synthesis and Antiviral Property of Allophenylnorstatine-based HIV Protease Inhibitors Incorporating D-cysteine Derivatives as P2/P3 Moieties.Bioorg.Med.Chem.Lett.2007,17,4213-4217.
[66]Matsumoto,H.;Matsuda,T;Nakata,S.;Mitoguchi,T.;Kimura,T;Hayashi,Y;Kiso,Y Synthesis and Biological Evaluation of Prodrug-Type Anti-HIV Agents:Ester Conjugates of Carboxylic Acid-Containing Dipeptide HIV Protease Inhibitors and a Reverse Transcriptase Inhibitor.Bioorg.Med.Chem.2001,9,417-430.
[67]Mimoto,T.;Imai,J.;Tanaka,S.;Hattori,N.;Takahashi,O.;Kisanuki,S.;Nagano,Y;Shintani,M.;Hayashi,H.;Sakikawa,H.;Akaji,K.;Kiso,Y Rational Design and Synthesis of a Novel Class of Active Site-Targeted HIV Protease Inhibitors Containing Phenylnorstatine or Allophenylnorstatine as a Transition-State Mimic.Chem.Pharm.Bull.1991,39,2465-2467.
[68]Mimoto,T.;Kato,R.;Takaku,H.;Nojima,S.;Terashima,K.;Misawa,S.;Fukazawa,T;Ueno,T.;Sato,H.;Shintani,M.;Kiso,Y;Hayashi,H.Structure-Activity Relationship of Small-Sized HIV Protease Inhibitors Containing Allophenylnorstatine.J.Med.Chem.1999,42,1789-1802.
[69]Baldwin,E.T.;Bhat,T.N.;Gulnik,S.;Liu B.;Topol I.;Kiso Y;Mimoto T;Mitsuya H.;Erickson J.W.Structure of HIV-1 Protease with KNI-272,a Tight-binding Transition-state Analog Containing Allophenylnorstatins.Structure 1995,3(6),581-590.
[70]Vega,S.;Kang,L.-W.;Velazquez-Campoy,A.;Kiso,Y;Amzel,L.M.;Freire,E.A Structure and Thermodynamic Escape Mechanism from a Drug Resistant Mutant of the HIV-1 Protease.Proteins 2004,55,594-602.
[71]Wang,Y.-X.;Freedberg,D.I.;Wingfield,P.T.;Stahl,S.J.;Kaufman,J.D.;Kiso,Y.;Bhat,T.N.;Erichson,J.W.;Torchia,D.A.Bound Water Molecules at the Interface between the HIV-1 Protease and a Potent Inhibitor,KNI-272,determined by NMR.J.Am.Chem.Soc.1996,118,12287-12290.
[72]Wang,Y.-X.;Freedberg,D.I.;Yamazaki,T.;Wingfield,P.T.;Stahl,S.J.;Kaufman,J.D.;Kiso,Y.;Torchia,D.A.Solution NMR Evidence that the HIV-1 Protease Catalytic Aspartyl Groups Have Different Ionization States in the Complex Formed with he Asymmetric Drug KNI-272.Biochemistry 1996,35,9945-9950.
[73]Kimura,T.;Nguyen,J.-T.;Maegawa,H.;Nishiyama,K.;Arii,Y.;Matsui,Y.;Hayashi,Y.;Kiso,Y.Chipping at Large,Potent Human T-cell Leukemia Virus Type 1 Protease Inhibitors to Uncover Smaller,Equipotent Inhibitors.Bioorg.Med.Chem.Lett.2007,17,3276-3280.
[74]Dunn,B.M.Structure and Mechanism of the Pepsin-Like Family of Aspartic Peptidases.Chem.Rev.2002,102,4431-4458.
[75]Bailey,P.D.An Introduction to Peptide Chemistry.ISBN 0-471-92348-6.John Wiley & Sons:Chichester,New York,Brisbane,Toronto,Singapore;Salle+Sauerlander:Aarau,Frankfurt am Main,Salzburg.1990,p114-149.
[76]Bodanszky,M.;Bodanszky,A.The Practice of Peptide Synthesis.ISBN 3-540-1347-9;0-387-13471-9.Springer-Verlag:Berlin,Heidelberg,New York,Tokyo 1984,p 9-31.
[77]Lippert,J.M.Amide Bond Formation by Using Amino Acid Fluorides.ARKIVOC 2005,xiv,87-95.
[78]Han,S.;Kim,Y.Recent Development of Peptide Coupling Reagents in Organic Synthesis.Tetrahedron 2004,60,2447-2467.
[79]Humphrey,J.;Chamberlin,A.R.Chemical Synthesis of Natural Product Peptides:Coupling Methods for the Incorporation of Noncoded Amino Acids into Peptides.Chem.Rev.1997,97,2243-2266.
[80]Pudhom,K.;Vilaivan,T.Pentafluorophenyl 4-Nitrobenzensulfonate as a Peptide Coupling Reagent.Synthetic Commun.2001,31(1),61-70.
[81]Carpino,L.A.;Xia,J.;El-Faham,A.3-Hydroxy-4-oxo-3,4-dihydro-5-azabenzo-1,2,3-triazene.J.Org.Chem.2004,69,54-61.
[82]Falkiewicz,B.Comparison of the Efficiency of Various Coupling System in the Acylation of Model Secondary Amines with Thymin-1-ylacetic Acid.Nucleic Acids Syrup.Ser.1999,42,153-154.
[83]Dormoy,J.;Castro,B.The Reaction of Hexamethyl Phosphoric Triamide(HMPT) with Phosphoryl Chloride:A Reexamination.Application to a Novel Preparation of BOP Reagent for Peptide Coupling.Tetrahedron Lett.1979,20,3321-3322.
[84]Hachmann,J.;Lebl,M.Search for Optimal Coupling Reagent in Multiple Peptide Synthesizer.Biopolymers(Pept.Sci.) 2006,84,340-347.