Andreas Schnapp

RATIONALE: The model most often used to study the pathogenesis of pulmonary fibroses is the bleomycin (BLM)-induced lung fibrosis model. Several treatments have been efficacious in this model, but not in the clinic. OBJECTIVES: To describe the time course of inflammation and fibrosis in the BLM model and to study the effect of timing of antiinflammatory and antifibrotic treatments on efficacy. METHODS AND MEASUREMENTS: Rats were given single intratracheal injections of BLM on Day 0. At specified time points, 10 rats were killed and their lungs studied for proinflammatory cytokines and for profibrotic growth factor mRNA. After a single intratracheal injection of BLM on Day 0, rats were treated from Day 1 or 10 daily with oral prednisolone (10 mg/kg) or oral imatinib mesylate (50 mg/kg) for 21 d. RESULTS: After BLM administration, the expression of inflammatory cytokines was elevated and returned to background levels at later time points. Profibrotic gene expression peaked between Days 9 and 14 and remained elevated till the end of the experiment, suggesting a "switch" between inflammation and fibrosis in this interval. Antiinflammatory treatment (oral prednisolone) was beneficial when commenced at Day 1, but had no effect if administered from Day 10 onward. However, imatinib mesylate was effective independently of the dosing regime. CONCLUSIONS: The response of the BLM model to antifibrotic or antiinflammatory interventions is critically dependent on timing after the initial injury.

Telomerase, a ribonucleoprotein acting as a reverse transcriptase, has been identified as a target for cancer drug discovery. The synthetic, non-nucleosidic compound, BIBR1532, is a potent and selective telomerase inhibitor capable of inducing senescence in human cancer cells (1Damm K. Hemmann U. Garin-Chesa P. Hauel N. Kauffmann I. Priepke H. Niestroj C. Daiber C. Enenkel B. Guilliard B. Lauritsch I. Müller E. Pascolo E. Sauter G. Pantic M. Martens U.M. Wenz C. Lingner J. Kraut N. Rettig W.J. Schnapp A. EMBO J. 2001; 20: 6958-6968Crossref PubMed Scopus (359) Google Scholar). In the present study, the mode of drug action was characterized. BIBR1532 inhibits the native and recombinant human telomerase, comprising the human telomerase reverse transcriptase and human telomerase RNA components, with similar potency primarily by interfering with the processivity of the enzyme. Enzyme-kinetic experiments show that BIBR1532 is a mixed-type non-competitive inhibitor and suggest a drug binding site distinct from the sites for deoxyribonucleotides and the DNA primer, respectively. Thus, BIBR1532 defines a novel class of telomerase inhibitor with mechanistic similarities to non-nucleosidic inhibitors of HIV1 reverse transcriptase. Telomerase, a ribonucleoprotein acting as a reverse transcriptase, has been identified as a target for cancer drug discovery. The synthetic, non-nucleosidic compound, BIBR1532, is a potent and selective telomerase inhibitor capable of inducing senescence in human cancer cells (1Damm K. Hemmann U. Garin-Chesa P. Hauel N. Kauffmann I. Priepke H. Niestroj C. Daiber C. Enenkel B. Guilliard B. Lauritsch I. Müller E. Pascolo E. Sauter G. Pantic M. Martens U.M. Wenz C. Lingner J. Kraut N. Rettig W.J. Schnapp A. EMBO J. 2001; 20: 6958-6968Crossref PubMed Scopus (359) Google Scholar). In the present study, the mode of drug action was characterized. BIBR1532 inhibits the native and recombinant human telomerase, comprising the human telomerase reverse transcriptase and human telomerase RNA components, with similar potency primarily by interfering with the processivity of the enzyme. Enzyme-kinetic experiments show that BIBR1532 is a mixed-type non-competitive inhibitor and suggest a drug binding site distinct from the sites for deoxyribonucleotides and the DNA primer, respectively. Thus, BIBR1532 defines a novel class of telomerase inhibitor with mechanistic similarities to non-nucleosidic inhibitors of HIV1 reverse transcriptase. reverse transcriptase human telomerase reverse transcriptase human telomerase RNA human immunodeficiency virus 2-((E)-3-naphthalen-2-yl-but-2-enoylamino)-benzoic acid telomeric repeat amplification protocol The reactivation of telomerase is a key requisite for human cancer cells to attain an unlimited proliferation potential and is regarded as an essential alteration in the physiology of the tumor cell to acquire malignant growth. (2Hanahan D. Weinberg R.A. Cell. 2002; 100: 57-70Abstract Full Text Full Text PDF Scopus (22628) Google Scholar, 3Bodnar A.G. Ouellette M. Frolkis M. Holt S.E. Chiu C.P. Morin G.B. Harley C.B. Shay J.W. Lichtsteiner S. Wright W.E. Science. 1998; 279: 349-352Crossref PubMed Scopus (4147) Google Scholar, 4Hahn W.C. Counter C.M. Lundberg A.S. Beijersbergen R.L. Brooks M.W. Weinberg R.A. Nature. 1999; 400: 464-468Crossref PubMed Scopus (1991) Google Scholar, 5Meyerson M. Counter C.M. Eaton E.N. Ellisen L.W. Steiner P. Caddle S.D. Ziaugra L. Beijersbergen R.L. Davidoff M.J. Liu Q. Bacchetti S. Haber D.A. Weinberg R.A. Cell. 1997; 90: 785-795Abstract Full Text Full Text PDF PubMed Scopus (1666) Google Scholar). The underlying concept, namely telomere maintenance by telomerase, has been demonstrated for 85–90% of human cancer specimens from a large range of different cancer types (6Shay J.W. Bacchetti S. Eur. J. Cancer. 1997; 33: 787-791Abstract Full Text PDF PubMed Scopus (2418) Google Scholar). Constitutive overexpression of the enzyme in various presenescent and normal cells conveyed an unlimited growth potential onto these cells (3Bodnar A.G. Ouellette M. Frolkis M. Holt S.E. Chiu C.P. Morin G.B. Harley C.B. Shay J.W. Lichtsteiner S. Wright W.E. Science. 1998; 279: 349-352Crossref PubMed Scopus (4147) Google Scholar), confirming further the role of telomerase in the immortalization process. In contrast, inhibition of telomerase results in telomere-shortening, subsequent growth arrest, and senescence in a wide range of tumor cell lines. This has been demonstrated by expressing a dominant-negative form of telomerase in immortal tumor cell lines (7Zhang X. Mar V. Zhou W. Harrington L. Robinson M.O. Genes Dev. 1999; 13: 2388-2399Crossref PubMed Scopus (562) Google Scholar, 8Hahn W.C. Stewart S.A. Brooks M.W. York S.G. Eaton E. Kurachi A. Beijersbergen R.L. Knoll J.H. Meyerson M. Weinberg R.A. Nat. Med. 1999; 5: 1164-1170Crossref PubMed Scopus (945) Google Scholar) and, pharmacologically, by the use of the small molecule telomerase inhibitor, BIBR1532 (1Damm K. Hemmann U. Garin-Chesa P. Hauel N. Kauffmann I. Priepke H. Niestroj C. Daiber C. Enenkel B. Guilliard B. Lauritsch I. Müller E. Pascolo E. Sauter G. Pantic M. Martens U.M. Wenz C. Lingner J. Kraut N. Rettig W.J. Schnapp A. EMBO J. 2001; 20: 6958-6968Crossref PubMed Scopus (359) Google Scholar). These data underscore that telomerase may represent a valuable target for novel antitumor therapies. Telomerase is a ribonucleoprotein that acts as a reverse transcriptase (RT)1 by using a small region of its RNA subunit, hTR, as a template for the synthesis of telomeric DNA (9Greider C.W. Blackburn E.H. Nature. 1989; 337: 331-337Crossref PubMed Scopus (1316) Google Scholar, 10Harrington L. Zhou W. McPhail T. Oulton R. Yeung D.S. Mar V. Bass M.B. Robinson M.O. Genes Dev. 1997; 11: 3109-3115Crossref PubMed Scopus (410) Google Scholar, 11Morin G.B. Cell. 1989; 59: 521-529Abstract Full Text PDF PubMed Scopus (1377) Google Scholar). Reverse transcription itself is catalyzed by the telomerase protein subunit, hTERT. Since catalytically active telomerase has been assembled from recombinant hTERT protein andin vitro transcribed hTR (12Beattie T.L. Zhou W. Robinson M.O. Harrington L. Curr. Biol. 1998; 8: 177-180Abstract Full Text Full Text PDF PubMed Scopus (323) Google Scholar, 13Weinrich S.L. Ma R. Pruzan L. Ouellette M. Tesmer V.M. Holt S.E. Bodnar A.G. Lichtsteiner S. Kim N.W. Trager J.B. Taylor R.D. Carlos R. Andrews W.H. Wright W.E. Shay J.W. Harley C.B. Morin G.B. Nat. Genet. 1997; 17: 498-502Crossref PubMed Scopus (862) Google Scholar), these subunits are regarded as the telomerase core enzyme. In vivo, however, human telomerase exists as a high molecular weight complex with an estimated molecular mass of 1000 KDa (14Ford L.P. Suh J.M. Wright W.E. Shay J.W. Mol. Cell. Biol. 2000; 20: 9084-9091Crossref PubMed Scopus (69) Google Scholar, 15Holt S.E. Aisner D.L. Baur J. Dy V.M. Tesmer M. Ouellette M. Trager J.B. Morin G.B. Toft D.O. Shay J.W. Wright W.E. White M.A. Genes Dev. 1999; 13: 817-826Crossref PubMed Scopus (477) Google Scholar, 16Mitchell J.R. Wood E. Collins K. Nature. 1999; 402: 551-555Crossref PubMed Scopus (911) Google Scholar, 17Schnapp G. Rodi H.P. Rettig W.J. Schnapp A. Damm K. Nucleic Acids Res. 1998; 26: 3311-3313Crossref PubMed Scopus (91) Google Scholar). This large size may be due to the multimeric nature of human telomerase and the association of the telomerase core components, hTERT and hTR, with several telomerase-associated proteins. These diverse proteins may play an important role in telomerase biogenesis, regulation and stability, or may modulate the interaction with telomeres in vivo; however, they are not considered to exert a direct function in catalysis (12Beattie T.L. Zhou W. Robinson M.O. Harrington L. Curr. Biol. 1998; 8: 177-180Abstract Full Text Full Text PDF PubMed Scopus (323) Google Scholar, 13Weinrich S.L. Ma R. Pruzan L. Ouellette M. Tesmer V.M. Holt S.E. Bodnar A.G. Lichtsteiner S. Kim N.W. Trager J.B. Taylor R.D. Carlos R. Andrews W.H. Wright W.E. Shay J.W. Harley C.B. Morin G.B. Nat. Genet. 1997; 17: 498-502Crossref PubMed Scopus (862) Google Scholar, 18Bachand F. Autexier C. J. Biol. Chem. 1999; 274: 38027-38031Abstract Full Text Full Text PDF PubMed Scopus (52) Google Scholar). In vitro telomerase is able to elongate a short single-stranded DNA in a processive manner by adding multiple TTAGGG repeats to the 3′-end of a suitable DNA primer. Since the enzyme appears to pause after synthesis of each set of six nucleotides representing a single telomeric repeat, a typical pattern of product bands spaced at six-nucleotide intervals is observed. Once the 5′ boundary of the template is copied the DNA substrate is thought to either translocate during processive synthesis, or it may dissociate from the enzyme. Thus, to allow addition of multiple telomeric repeats, translocation and re-initiation must take place after each cycle of template copying. The mechanisms involved are not elucidated yet, but a critical factor could be the dimeric nature of human telomerase with two hTERT and two hTR molecules present per functional telomerase complex (19Wenz C. Enenkel B. Amacker M. Kelleher C. Damm K. Lingner J. EMBO J. 2001; 20: 3526-3534Crossref PubMed Scopus (134) Google Scholar, 20Beattie T.L. Zhou W. Robinson M.O. Harrington L. Mol. Cell. Biol. 2001; 21: 6151-6160Crossref PubMed Scopus (120) Google Scholar). Because of the structural and mechanistic similarity between hTERT and reverse transcriptases, it has been hypothesized that known reverse transcriptase inhibitors may potently inhibit human telomerase. HIV1-RT has been successfully inhibited by nucleoside analogs, which bind to the dNTP binding site (21Huang H. Chopra R. Verdine G.L. Harrison S.C. Science. 1998; 282: 1669-1675Crossref PubMed Scopus (1360) Google Scholar) and by non-nucleoside inhibitors (NNRTI), which bind to a hydrophobic pocket near the catalytic center resulting in a distortion of the active site (22Gu Z. Li Y. Quan Z. Arts E.J. Wainberg M.A. J. Biol. Chem. 1995; 270: 31046-31051Abstract Full Text Full Text PDF PubMed Scopus (37) Google Scholar, 23Kohlstaedt L.A. Wang J. Friedman J.M. Rice P.A. Steitz T.A. Science. 1992; 256: 1783-1790Crossref PubMed Scopus (1763) Google Scholar, 24Esnouf R. Ren J. Ross C. Jones Y. Stammers D. Stuart D. Nat. Struct. Biol. 1995; 2: 303-308Crossref PubMed Scopus (450) Google Scholar). However, all NNRTI and nucleoside analog inhibitors of HIV1-RT tested were found to be inactive or to exhibit only weak inhibitory activity toward human telomerase (25Fletcher T.M. Salazar M. Chen S.F. Biochemistry. 1996; 35: 15611-15617Crossref PubMed Scopus (77) Google Scholar, 26Strahl C. Blackburn E.H. Mol. Cell. Biol. 1996; 16: 53-65Crossref PubMed Scopus (358) Google Scholar, 27Tendian S.W. Parker W.B. Mol. Pharmacol. 2000; 57: 695-699Crossref PubMed Scopus (38) Google Scholar), suggesting that structural differences between these two families of reverse transcriptases are sufficient to allow specificity of the inhibitors. Additional strategies for inhibition of telomerase have been explored, including antisense approaches directed against hTR (28Bisoffi M. Chakerian A.E. Fore M.L. Bryant J.E. Hernandez J.P. Moyzis R.K. Griffith J.K. Eur. J. Cancer. 1998; 34: 1242-1249Abstract Full Text Full Text PDF PubMed Scopus (45) Google Scholar, 29Norton J.C. Piatyszek M.A. Wright W.E. Shay J.W. Corey D.R. Nat. Biotechnol. 1996; 14: 615-619Crossref PubMed Scopus (349) Google Scholar), compounds targeting telomeric DNA (30Mergny J.L. Helene C. Nat. Med. 1998; 4: 1366-1367Crossref PubMed Scopus (381) Google Scholar, 31Sun D. Thompson B. Cathers B.E. Salazar M. Kerwin S.M. Trent J.O. Jenkins T.C. Neidle S. Hurley L.H. J. Med. Chem. 1997; 40: 2113-2116Crossref PubMed Scopus (739) Google Scholar), and small molecule drugs (32White L.K. Wright W.E. Shay J.W. Trends Biotechnol. 2001; 19: 114-120Abstract Full Text Full Text PDF PubMed Scopus (197) Google Scholar). In the present study, we present the initial characterization of the mode of telomerase inhibition by BIBR1532, a synthetic small molecule inhibitor of human telomerase (1Damm K. Hemmann U. Garin-Chesa P. Hauel N. Kauffmann I. Priepke H. Niestroj C. Daiber C. Enenkel B. Guilliard B. Lauritsch I. Müller E. Pascolo E. Sauter G. Pantic M. Martens U.M. Wenz C. Lingner J. Kraut N. Rettig W.J. Schnapp A. EMBO J. 2001; 20: 6958-6968Crossref PubMed Scopus (359) Google Scholar). Deoxyribonucleotides were from Amersham Biosciences. 1,4-Dithiothreitol was from Roche Diagnostics, and phenylmethylsulfonyl fluoride was from Invitrogen. [α-33P]dCTP (1 mCi/100 μl) was purchased from Hartmann Analytic. The PCR primer forward (tea-fw: 5′-CAT ACT GGC GAC CAG AGT T-3′) and reverse (tea-rev: 5′-GGC GCG CCC TTA CCC TTA CCC TTA CCC TAA-3′) were from Carl Roth GmbH. Crude HeLa nuclear extracts (Computer Cell Culture Center, Seneffe, Belgium) were enriched for telomerase activity with a one-step chromatography on Q-Sepharose column (HiTrap Q HP, Amersham Biosciences). The buffer used was 20 mm Tris-Cl (pH 8.0), 100 μm EGTA, 100 μm EDTA, 1 mmMgCl2, 10% (w/v) glycerol, complemented with different concentrations of KCl (BCE100, 100 mm; BCE250, 250 mm; BCE500, 500 mm; BCE1000, 1 m). The 1-ml column was equilibrated in BCE100 buffer. The following steps were carried at 4 °C. 2 mg of HeLa nuclear extract was diluted in a large volume of BCE100 and loaded twice on the column at 0.5 ml/min. The column was washed at 0.5 ml/min with 4 volumes of BCE100 and 3 volumes of BCE250. Most of the proteins were eluted by washing with 4 volumes of BCE500. Telomerase activity was as 1-ml by with volumes of and against BCE100 500 μm and 250 μm phenylmethylsulfonyl The were for protein with a and for telomerase activity in the N.W. Piatyszek M.A. Harley C.B. Wright W.E. S.L. Shay J.W. Science. PubMed Scopus Google Scholar). Telomerase activity was with hTERT in cells andin vitro transcribed hTERT with hTR was as chromatography with an directed against the hTR (19Wenz C. Enenkel B. Amacker M. Kelleher C. Damm K. Lingner J. EMBO J. 2001; 20: 3526-3534Crossref PubMed Scopus (134) Google Scholar). the direct telomerase with the telomerase, of extract was with different concentrations of BIBR1532 in a volume of 20 on 20 of the was and the was by the to °C. The concentrations in the were mm Tris-Cl (pH 1 mm 1 mm EGTA, 1 mm 1 mm μm mm of and μm Biosciences). the recombinant of telomerase μm were in a volume of mm (pH 1 mm 1 mm mm 1 mm 1 mm μm of Amersham and μm The was by at for 2 and by addition of of in mm Tris-Cl (pH and 20 mm and for 20 at °C. were by adding of in mm Tris-Cl (pH and for a at °C. DNA was by and and the were on an or were to a and the results were a The was as G. Rodi H.P. Rettig W.J. Schnapp A. Damm K. Nucleic Acids Res. 1998; 26: 3311-3313Crossref PubMed Scopus (91) Google Scholar, N.W. Piatyszek M.A. Harley C.B. Wright W.E. S.L. Shay J.W. Science. PubMed Scopus Google Scholar). In BIBR1532 has inhibitory after the telomerase the were each present at μm and the primer at The telomerase and BIBR1532 were for on in buffer. addition of different concentrations of the the was by at for by at for and on with the PCR the was to a of μm for each dNTP and for the DNA primer. The PCR was and PCR was for at at at The of was either by after with acid or on a after on a the of BIBR1532 were carried in in the of concentrations of substrate and were at and the results of were used for further The were with on and the of was by the was against the were as the of substrate to The inhibition were from and and to the of the respectively. BIBR1532 has been identified as a potent and selective inhibitor of human telomerase (1Damm K. Hemmann U. Garin-Chesa P. Hauel N. Kauffmann I. Priepke H. Niestroj C. Daiber C. Enenkel B. Guilliard B. Lauritsch I. Müller E. Pascolo E. Sauter G. Pantic M. Martens U.M. Wenz C. Lingner J. Kraut N. Rettig W.J. Schnapp A. EMBO J. 2001; 20: 6958-6968Crossref PubMed Scopus (359) Google Scholar). a of the of action by compound, the mode of telomerase inhibition was in further using native enzyme enriched from HeLa cell nuclear extract as as recombinant enzyme from recombinant hTERT and in The of BIBR1532 on telomerase activity was using two a G.B. Cell. 1989; 59: 521-529Abstract Full Text PDF PubMed Scopus (1377) Google Scholar) on a direct of enzyme activity and the N.W. Piatyszek M.A. Harley C.B. Wright W.E. S.L. Shay J.W. Science. PubMed Scopus Google Scholar), which an amplification in the native enzyme in the concentrations of BIBR1532 inhibit in a manner of the by a of at concentrations of the inhibitor, the synthesis of appears to be the synthesis of of telomerase activity is in a with the of the primer the synthesis of is inhibited at concentrations of BIBR1532 allow a the of was by and were for each in the for the product which to the two of template is The of the two and is inhibited with of and 100 respectively. BIBR1532 on the telomerase core active telomerase was by cell recombinant hTERT vitro transcribed telomerase were by RNA and the eluted enzyme was tested in the primer in the enzyme catalyzed the of the repeat for human telomerase with the product bands to the of template copying. recombinant telomerase was inhibited by BIBR1532 for the native the of is the of the The which to the cycle of template is only inhibited at concentrations of BIBR1532 1 the of the and to and of template is inhibited with of in the of high concentrations of BIBR1532, the of were observed. Thus, BIBR1532 not inhibit the catalytic steps during a single of template copying. the mode of inhibition by BIBR1532 as a function of the for telomerase and a DNA primer, a of enzyme experiments were The for the of primer were in an initial in the of substrate concentrations and of native telomerase. in a between enzyme and the of telomerase was for for the subsequent experiments between 4 and were and were for different substrate concentrations in the or of in a was telomerase activity was as a function of the DNA primer in the of the inhibitor The was with primer concentrations In the of of BIBR1532, a in was a for a non-competitive the inhibitor tested (1 was by The data were used to the of the DNA primer in the and in the of BIBR1532 and to the binding of the inhibitor in the and in the of the DNA primer. in the and for the DNA primer were not suggesting that BIBR1532 not the binding of the DNA primer to the enzyme. However, a but of was a of BIBR1532 to the enzyme to the primer The and the resulting were for each of the deoxyribonucleotides in the or of BIBR1532 and in for each of the a was in the of BIBR1532, a non-competitive mode of inhibition for the deoxyribonucleotides The for each of the in the of the inhibitor 1 μm BIBR1532, for and to and suggesting for each dNTP a to the The of BIBR1532 were to be for the enzyme and a complex This a binding of the drug to the enzyme and a to each In the these in the of the and the the was is a mixed-type non-competitive inhibitor for the binding of of in of BIBR1532 in the or the of the The in the for the and a in a mixed-type with different binding sites for the and the inhibitor, but with between the binding of each W.C. and of and Scholar). The of the of enzyme by small molecule drug is of as for the drugs (22Gu Z. Li Y. Quan Z. Arts E.J. Wainberg M.A. J. Biol. Chem. 1995; 270: 31046-31051Abstract Full Text Full Text PDF PubMed Scopus (37) Google Scholar, 23Kohlstaedt L.A. Wang J. Friedman J.M. Rice P.A. Steitz T.A. Science. 1992; 256: 1783-1790Crossref PubMed Scopus (1763) Google Scholar). In we show that BIBR1532 telomerase core as telomerase from hTR and recombinant hTERT is inhibited by BIBR1532 with with the native enzyme from tumor In BIBR1532 a non-competitive mode of which is distinct from the inhibition using compounds or antisense for the native and the recombinant enzyme data show that BIBR1532 not but inhibits the of In the inhibitor to an in the of TTAGGG the of six however, is This that BIBR1532 not the catalytic steps involved in template but the of the DNA substrate after its to the of the Thus, BIBR1532 may translocation of the enzyme DNA substrate complex or may between DNA substrate and the enzyme of template copying. these steps are to telomerase, may the high of the In a the of inhibition by BIBR1532 were only a inhibition of the binding of the DNA primer in the of However, BIBR1532 the for binding of deoxyribonucleotides the of the enzyme for This inhibition to a mixed-type non-competitive in which the enzyme has but binding sites for deoxyribonucleotides and may an the binding of the substrate or the drug a of the enzyme interfering with the binding of the the binding site of the drug and the binding site of the deoxyribonucleotides are in or a for the binding The data not an inhibition and we the with telomerase on enzyme and function are known HIV1 reverse transcriptase. The of enzyme is as a the as and with the catalytic center the L.A. Wang J. Friedman J.M. Rice P.A. Steitz T.A. Science. 1992; 256: 1783-1790Crossref PubMed Scopus (1763) Google Scholar). are important for HIV1-RT The non-nucleosidic drug inhibits the translocation of (22Gu Z. Li Y. Quan Z. Arts E.J. Wainberg M.A. J. Biol. Chem. 1995; 270: 31046-31051Abstract Full Text Full Text PDF PubMed Scopus (37) Google Scholar). experiments that a hydrophobic pocket between the and the of the but not with the DNA binding site L.A. Wang J. Friedman J.M. Rice P.A. Steitz T.A. Science. 1992; 256: 1783-1790Crossref PubMed Scopus (1763) Google Scholar). of the drug may either of the catalytic or may to the catalytic the similarity between telomerase and HIV1 reverse transcriptase is key in and of catalysis it has been that in that are between and reverse transcriptases or activity in types of or similar on processivity S.L. Ma R. Pruzan L. Ouellette M. Tesmer V.M. Holt S.E. Bodnar A.G. Lichtsteiner S. Kim N.W. Trager J.B. Taylor R.D. Carlos R. Andrews W.H. Wright W.E. Shay J.W. Harley C.B. Morin G.B. Nat. Genet. 1997; 17: 498-502Crossref PubMed Scopus (862) Google Scholar, Y. C. P. Wainberg M.A. Nucleic Acids Res. 1998; 26: PubMed Scopus Google Scholar, T.M. J. Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar, J. A. M. V. Science. 1997; PubMed Scopus Google Scholar, Liu J.K. Collins K. EMBO J. 2000; 19: PubMed Scopus Google Scholar, D. J. Biol. Chem. 2001; Full Text Full Text PDF PubMed Scopus (38) Google Scholar). a to the processivity of primer and that telomerase, as its may hydrophobic between the and which be for binding of small molecule inhibitors D. J. Biol. Chem. 2001; Full Text Full Text PDF PubMed Scopus (38) Google Scholar, Y. Mol. Cell. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar). the similarities in the of action of on HIV1 reverse transcriptase and BIBR1532 on human telomerase with the structural and mechanistic similarities of are However, a of the molecular of BIBR1532 inhibition the of the HIV1-RT a inhibitory has been and were used (22Gu Z. Li Y. Quan Z. Arts E.J. Wainberg M.A. J. Biol. Chem. 1995; 270: 31046-31051Abstract Full Text Full Text PDF PubMed Scopus (37) Google Scholar). it be of to inhibition of telomerase by BIBR1532 is with in in vitro in the of telomerase inhibitors. the of the of for and The of Guilliard is