Effective lowly cytotoxic analogs of an HIV-cell fusion inhibitor, T22 ([Tyr5,12, Lys7]-polyphemusin II)

Tamamura, Hirokazu; Arakaki, Rieko; Funakoshi, Hanae; Imai, Makoto; Otaka, Akira; Ibuka, Toshiro; Nakashima, Hideki; Murakami, Tsutomu; Waki, Michinori; Matsumoto, Aki; Yamamoto, Naoki; Fujii, Nobutaka

doi:10.1016/s0968-0896(97)10037-2

Cited by 55 publications

(49 citation statements)

References 25 publications

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“…10 The polyphemusin II peptide derivatives were TC140012, T140, and T134. 12 . All peptides were synthesized by Mimotopes (Clayton, VIC, Australia).…”

Section: Chemokines Peptides and Antibodiesmentioning

confidence: 99%

“…These peptides can also effectively block the binding of SDF-1 to T cells at nanomolar concentrations. 12 Bicyclams are also potent and selective inhibitors of HIV binding to CXCR4. 13 AMD3100, a bicyclam with high anti-viral activity against CXCR4-specific strains of HIV, has been recently tested in a phase I clinical trial 14 and was well tolerated without any significant toxicity.…”

Section: Introductionmentioning

confidence: 99%

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Effects of inhibitors of the chemokine receptor CXCR4 on acute lymphoblastic leukemia cells in vitro

et al. 2003

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Stromal cell-derived factor-1 (SDF-1) is a key regulator of the behavior of normal and leukemic precursor-B (pre-B) cells. It is possible that inhibiting SDF-1-driven processes in pre-B acute lymphoblastic leukemia (ALL) may have therapeutic implications. In this study, we examined the ability of SDF-1 inhibitors to modulate pre-B ALL cell responses to SDF-1, including chemotaxis, migration into bone marrow stroma, and stromasupported survival and proliferation on human bone marrow stromal layers. The polyphemusin II-derived inhibitors, T140, TC140012, and T134, and the bicyclam AMD3100, effectively inhibited binding of the anti-CXCR4 monoclonal antibody 12G5 on the pre-B ALL cell line NALM6, with IC 50 values of 0.9, 0.9, 0.9, and 1.9 nM, respectively. Similar results were obtained with ALL samples. T140 (0.1 lM) and AMD3100 (1 lM) completely blocked SDF-1-induced chemotaxis and attenuated the migration of pre-B ALL cells into bone marrow stromal layers. AMD3100 and TC140012 at a concentration of 50 lM significantly inhibited stroma-dependent proliferation of six and four of the eight cases tested, respectively, without reducing the cell viability. In addition, AMD3100 and TC140012 enhanced the cytotoxic and antiproliferative effects of the cytotoxic agents vincristine and dexamethasone. The ability of SDF-1 inhibitors to modulate these biologically important functions of leukemic cells warrants further investigation.

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“…10 The polyphemusin II peptide derivatives were TC140012, T140, and T134. 12 . All peptides were synthesized by Mimotopes (Clayton, VIC, Australia).…”

Section: Chemokines Peptides and Antibodiesmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Effects of inhibitors of the chemokine receptor CXCR4 on acute lymphoblastic leukemia cells in vitro

et al. 2003

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“…AMD3100 and AMD2763 were kindly provided by Gary Bridger and Geoffrey Henson (AnorMED, Langley, British Columbia, Canada) and were synthesized as described previously (5). The compounds T134 and T140 (2,26,27) were kindly provided by H. Nakashima (Kagoshima University, Japan). 3Ј-Azido-3Ј-deoxythymidine (AZT) was synthesized by the method described by Horwitz et al (17).…”

Section: Methodsmentioning

confidence: 99%

“…The bicyclam AMD3100 was introduced in phase II clinical trials (30), but development was interrupted due to cardiac problems. The synthetic peptide T22, an 18-mer (22), and its shortened successors T134 and T140 (2,26,27) act as CXCR4 antagonists due to their positive charges.…”

mentioning

confidence: 99%

env Chimeric Virus Technology for Evaluating Human Immunodeficiency Virus Susceptibility to Entry Inhibitors

Fikkert

Cherepanov

Laethem

et al. 2002

Antimicrob Agents Chemother

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We describe the development of chimeric virus technology (CVT) for human immunodeficiency virus (HIV) type 1 (HIV-1) env genes gp120, gp41, and gp160 for evaluation of the susceptibilities of HIV to entry inhibitors. This env CVT allows the recombination of env sequences derived from different strains into a proviral wild-type HIV-1 clone (clone NL4.3) from which the corresponding env gene has been deleted. An HIV-1 strain (strain NL4.3) resistant to the fusion inhibitor T20 (strain NL4.3/T20) was selected in vitro in the presence of T20. AMD3100-resistant strain NL3.4 (strain NL4.3/AMD3100) was previously selected by De Vreese et al. (K. De Vreese et al., J. Virol. 70:689-696, 1996). NL4.3/AMD3100 contains several mutations in its gp120 gene (De Vreese et al., J. Virol. 70:689-696, 1996), whereas NL4.3/T20 has mutations in both gp120 and gp41. Phenotypic analysis revealed that NL4.3/AMD3100 lost its susceptibility to dextran sulfate, AMD3100, AMD2763, T134, and T140 but not its susceptibility to T20, whereas NL4.3/T20 lost its susceptibility only to the inhibitory effect of T20. The recombination of gp120 of NL4.3/AMD3100 and gp41 of NL4.3/T20 or recombination of the gp160 genes of both strains into a wild-type background reproduced the phenotypic (cross-)resistance profiles of the corresponding strains selected in vitro. These data imply that mutations in gp120 alone are sufficient to reproduce the resistance profile of NL4.3/AMD3100. The same can be said for gp41 in relation to NL4.3/T20.In conclusion, we demonstrate the use of env CVT as a research tool in the delineation of the region important for the phenotypic (cross-)resistance of HIV strains to entry inhibitors. In addition, we obtained a proof of principle that env CVT can become a helpful diagnostic tool in assessments of the phenotypic resistance of clinical HIV isolates to HIV entry inhibitors.The treatment of human immunodeficiency virus (HIV) infection used at present focuses primarily on inhibition of the viral enzymes reverse transcriptase (RT) and protease (PRO). These compounds are not always able to suppress virus replication completely. In many patients, residual replication in the presence of the selective pressure of antiviral drugs allows the emergence of drug-resistant strains, finally resulting in therapeutic failure (19,28). Therefore, the development of new drugs that preferentially act on new targets in the HIV replication cycle is of high priority in anti-HIV research. A potentially powerful target in addition to RT and PRO is the first event in the virus replicative cycle, HIV entry. HIV entry involves the interaction of the viral protein gp120 with the CD4 receptor on the surface of the target cell and the subsequent interaction of gp120 with the coreceptor CCR5 (for strains using the CCR5 receptor) or CXCR4 (for strains using the CXCR4 receptor). This interaction results in a conformational change in viral glycoprotein gp41, in which the interaction of heptad region 1 (HR1) and HR2 is followed by fusion of the virus with the cel...

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“…Through quantitative structure activity relationship (QSAR) analysis, pharmacophores or regions and properties of the T22 molecular structure which were essential to its interaction with CXCR4 were identified and investigated through a series of analog peptide structures [192][193][194], allowing eventual downsizing of the original 19-mer polypeptide to a smaller 14-mer peptide, T140 [195]. Subsequent structure-activity relationship analysis of T140 [127,175,[196][197][198][199][200], allowed additional pharmacophore development based on this structure FN [30,[201][202][203][204].…”

Section: Structure Based Drug Design Is An Effective Technique For Idmentioning

confidence: 99%

Structure-based design of inhibitors of CXCR4.

Meier¹

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Effective lowly cytotoxic analogs of an HIV-cell fusion inhibitor, T22 ([Tyr5,12, Lys7]-polyphemusin II)

Cited by 55 publications

References 25 publications

Effects of inhibitors of the chemokine receptor CXCR4 on acute lymphoblastic leukemia cells in vitro

Effects of inhibitors of the chemokine receptor CXCR4 on acute lymphoblastic leukemia cells in vitro

env Chimeric Virus Technology for Evaluating Human Immunodeficiency Virus Susceptibility to Entry Inhibitors

Structure-based design of inhibitors of CXCR4.

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