Design and Evaluation of Sifuvirtide, a Novel HIV-1 Fusion Inhibitor

Abstract

Enfuvirtide (T20) is the first and only HIV-1 fusion inhibitor approved for clinical use, but it can easily induce drug resistance limiting its practical application. A novel anti-HIV peptide, termed sifuvirtide, was designed based on the three-dimensional structure of the HIV-1 gp41 fusogenic core conformation. Here we report its in vitro anti-HIV potency, its mechanism of action, as well as the results from Phase Ia clinical studies. We demonstrated that sifuvirtide inhibited HIV-1-mediated cell-cell fusion in a dose-dependent manner and exhibited high potency against infections by a wide range of primary and laboratory-adapted HIV-1 isolates from multiple genotypes with R5 or X4 phenotypes. Notably, sifuvirtide was also highly effective against T20-resistant strains. Unlike T20, sifuvirtide could efficiently block six-helix bundle formation in a dominant negative fashion. These results suggest that sifuvirtide has a different mechanism of action from that of T20. Phase Ia clinical studies of sifuvirtide (FS0101) in 60 healthy individuals demonstrated good safety, tolerability, and pharmacokinetic profiles. A single dose regimen (5, 10, 20, 30, and 40 mg) by subcutaneous injection once daily at abdominal sites was well tolerated without serious adverse events. Pharmacokinetic studies of single and multiple administration of sifuvirtide showed that its decay half-lives were 20.0 ± 8.6 h and 26.0 ± 7.9 h, respectively. In summary, sifuvirtide has potential to become an ideal fusion inhibitor for treatment of HIV/AIDS patients, including those with HIV-1 strains resistant to T20. Enfuvirtide (T20) is the first and only HIV-1 fusion inhibitor approved for clinical use, but it can easily induce drug resistance limiting its practical application. A novel anti-HIV peptide, termed sifuvirtide, was designed based on the three-dimensional structure of the HIV-1 gp41 fusogenic core conformation. Here we report its in vitro anti-HIV potency, its mechanism of action, as well as the results from Phase Ia clinical studies. We demonstrated that sifuvirtide inhibited HIV-1-mediated cell-cell fusion in a dose-dependent manner and exhibited high potency against infections by a wide range of primary and laboratory-adapted HIV-1 isolates from multiple genotypes with R5 or X4 phenotypes. Notably, sifuvirtide was also highly effective against T20-resistant strains. Unlike T20, sifuvirtide could efficiently block six-helix bundle formation in a dominant negative fashion. These results suggest that sifuvirtide has a different mechanism of action from that of T20. Phase Ia clinical studies of sifuvirtide (FS0101) in 60 healthy individuals demonstrated good safety, tolerability, and pharmacokinetic profiles. A single dose regimen (5, 10, 20, 30, and 40 mg) by subcutaneous injection once daily at abdominal sites was well tolerated without serious adverse events. Pharmacokinetic studies of single and multiple administration of sifuvirtide showed that its decay half-lives were 20.0 ± 8.6 h and 26.0 ± 7.9 h, respectively. In summary, sifuvirtide has potential to become an ideal fusion inhibitor for treatment of HIV/AIDS patients, including those with HIV-1 strains resistant to T20. Currently, over 33 millions people worldwide are living with human immunodeficiency virus (HIV), 3The abbreviations used are: HIV, human immunodeficiency virus; NHR, N-terminal heptad repeat; 6-HB, six-helix bundle structure; CHR, C-terminal heptad repeat; SFT, sifuvirtide; ELISA, enzyme-linked immunosorbent assay; PBS, phosphate-buffered saline; LUV, large unilamellar vesicle; POPC, 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine. 3The abbreviations used are: HIV, human immunodeficiency virus; NHR, N-terminal heptad repeat; 6-HB, six-helix bundle structure; CHR, C-terminal heptad repeat; SFT, sifuvirtide; ELISA, enzyme-linked immunosorbent assay; PBS, phosphate-buffered saline; LUV, large unilamellar vesicle; POPC, 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine. and around 20 million people have died from AIDS (www.unaids.org). Due to lack of effective vaccines, development of novel anti-HIV drugs is critical to save lives of people with HIV infection. So far, 31 anti-HIV drugs and combinations have been approved for clinical use, and most of them belong to reverse transcriptase inhibitors and protease inhibitors (www.fda.gov). Application of these drugs in various combinations, known as highly active antiretroviral therapy, has significantly reduced the morbidity and mortality of HIV/AIDS (1Palella Jr., F.J. Delaney K.M. Moorman A.C. Loveless M.O. Fuhrer J. Satten G.A. Aschman D.J. Holmberg S.D. N. Engl. J. Med. 1998; 338: 853-860Crossref PubMed Scopus (8458) Google Scholar). However, more and more HIV/AIDS patients have failed to respond to highly active antiretroviral therapy regimens because of the emergence of variants resistant to the current treatment regimens (2Hogg R.S. Bangsberg D.R. Lima V.D. Alexander C. Bonner S. Yip B. Wood E. Dong W.W. Montaner J.S. Harrigan P.R. PLoS. Med. 2006; 3: e356Crossref PubMed Scopus (142) Google Scholar, 3Pillay D. Taylor S. Richman D.D. Rev. Med. Virol. 2000; 10: 231-253Crossref PubMed Scopus (104) Google Scholar). Therefore, the development of new classes of anti-HIV drugs is urgently needed. The envelope glycoprotein of HIV-1 that mediates the attachment and fusion of the viral envelope and the cellular membrane represents a major target for the development of novel antiretroviral therapeutics (4Este J.A. Telenti A. Lancet. 2007; 370: 81-88Abstract Full Text Full Text PDF PubMed Scopus (242) Google Scholar, 5Moore J.P. Doms R.W. Proc. Natl. Acad. Sci. U. S. A. 2003; 100: 10598-10602Crossref PubMed Scopus (256) Google Scholar). HIV-1 envelope glycoprotein is a trimer, each of which consists of two non-covalently associated subunits gp120 and gp41 (6Hunter E. Swanstrom R. Curr. Top. Microbiol. Immunol. 1990; 157: 187-253PubMed Google Scholar, 7Wyatt R. Sodroski J. Science. 1998; 280: 1884-1888Crossref PubMed Scopus (1295) Google Scholar). Membrane fusion is triggered by the binding of gp120 on the virus initially with the CD4 molecule and subsequently with a chemokine receptor (CCR5 or CXCR4) on the surface of the target cell (8Berger E.A. Murphy P.M. Farber J.M. Annu. Rev. Immunol. 1999; 17: 657-700Crossref PubMed Scopus (1865) Google Scholar, 9Doms R.W. Moore J.P. J. Cell Biol. 2000; 151: F9-F14Crossref PubMed Google Scholar). These interactions result in a cascade of conformational changes that lead to the formation of a pre-hairpin intermediate of gp41 in which the hydrophobic N-terminal heptad repeat (NHR) are exposed and allows the fusion peptides to insert into the target cell membrane (5Moore J.P. Doms R.W. Proc. Natl. Acad. Sci. U. S. A. 2003; 100: 10598-10602Crossref PubMed Scopus (256) Google Scholar, 7Wyatt R. Sodroski J. Science. 1998; 280: 1884-1888Crossref PubMed Scopus (1295) Google Scholar). This transient gp41 intermediate then refolds into a stabilized trimer of hairpins, also called six-helix bundle structure (6-HB), which brings the close proximity of the viral envelope and the target cell membrane and results in the completion of the fusion process. Crystallographic and NMR studies show that the core of the hairpin consists of a parallel trimeric coiled-coil of NHR with the C-terminal heptad repeat (CHR) wrapped on the outside in an anti-parallel fashion (10Chan D.C. Fass D. Berger J.M. Kim P.S. Cell. 1997; 89: 263-273Abstract Full Text Full Text PDF PubMed Scopus (1822) Google Scholar, 11Tan K. Liu J. Wang J. Shen S. Lu M. Proc. Natl. Acad. Sci. U. S. A. 1997; 94: 12303-12308Crossref PubMed Scopus (517) Google Scholar, 12Weissenhorn W. Dessen A. Harrison S.C. Skehel J.J. Wiley D.C. Nature. 1997; 387: 426-430Crossref PubMed Scopus (1454) Google Scholar). In addition, this structure feature has been found in the fusion-mediating subunits of other enveloped viral glycoproteins such as the S2 subunit of SARS corona virus, the GP2 subunits of Ebola virus, the HA2 subunit of influenza virus, the F1 subunits of the paramyxovirus simian virus 5 and human T cell lymphotropic virus type I, and the TM subunits of retroviruses simian immunodeficiency virus, HIV-2, Moloney murine leukemia virus, and human respiratory syncytial virus-1 (13Eckert D.M. Kim P.S. Annu. Rev. Biochem. 2001; 70: 777-810Crossref PubMed Scopus (1131) Google Scholar). Inhibitors capable of disrupting the fusion process hold great promise for clinical antiviral therapeutics. Extensive efforts are being made to develop novel peptide-based as well as small molecule inhibitors targeting the discrete regions of the prehairpin intermediate during the fusion step (14Leonard J.T. Roy K. Curr. Med. Chem. 2006; 13: 911-934Crossref PubMed Scopus (36) Google Scholar, 15Liu S. Wu S. Jiang S. Curr. Pharm. Des. 2007; 13: 143-162Crossref PubMed Scopus (122) Google Scholar). In general, two major classes of such inhibitors have been described. The first one targets the NHR trimeric coiled-coil either by competitive binding with viral intrinsic CHR or by forming a heterotrimeric NHR with mutated NHR whereby disrupting the subsequent binding with native CHR (15Liu S. Wu S. Jiang S. Curr. Pharm. Des. 2007; 13: 143-162Crossref PubMed Scopus (122) Google Scholar, 16Bewley C.A. Louis J.M. Ghirlando R. Clore G.M. J. Biol. Chem. 2002; 277: 14238-14245Abstract Full Text Full Text PDF PubMed Scopus (128) Google Scholar, 17Debnath A.K. Expert. Opin. Investig. Drugs. 2006; 15: 465-478Crossref PubMed Scopus (17) Google Scholar). For examples, the peptides derived from the CHR such as and its demonstrated anti-HIV in and has been approved for clinical A of mutated NHR peptides by at and of the of the NHR trimeric coiled-coil were also demonstrated anti-HIV C.A. Louis J.M. Ghirlando R. Clore G.M. J. Biol. Chem. 2002; 277: 14238-14245Abstract Full Text Full Text PDF PubMed Scopus (128) Google Scholar). molecule inhibitors targeting the by the NHR are also being (15Liu S. Wu S. Jiang S. Curr. Pharm. Des. 2007; 13: 143-162Crossref PubMed Scopus (122) Google Scholar, 17Debnath A.K. Expert. Opin. Investig. Drugs. 2006; 15: 465-478Crossref PubMed Scopus (17) Google Scholar). The targets the CHR of A of this is a in which only one of the in the structure is exposed Kim P.S. Science. 2001; PubMed Scopus Google Scholar). In addition, a NHR trimeric coiled-coil such as and has also been to HIV fusion in in vitro J.M. C.A. Clore G.M. J. Biol. Chem. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar). it has been demonstrated that different classes of inhibitors targeting the NHR and CHR, and other classes of antiretroviral can in viral in vitro and in E. Louis J.M. C.A. Clore G.M. J. Biol. 2006; PubMed Scopus Google Scholar). on the three-dimensional of HIV-1 we have designed a novel anti-HIV peptide, sifuvirtide This inhibitor has been with different in to T20, and is in and and structure with the native CHR However, of these sifuvirtide is different from in and from in we report its in vitro potency, its mechanism of action, and the results from Phase Ia clinical studies. and clinical Phase Ia (FS0101) was designed to sifuvirtide for its safety, tolerability, and pharmacokinetic in 60 healthy were healthy with of and of were in good healthy and were to or was from the the and the were and approved by the at the T20, and were on a by high and for by and of the peptides were by and a of and based on the of and the peptides respectively. was as Liu S. W. Lu D. D.J. A.K. Jiang S. J. Biol. Chem. 2007; Full Text Full Text PDF PubMed Scopus Google Scholar). an was with the of or or sifuvirtide at for The was in and The and as well as sifuvirtide were also of these peptides and were on a at a and a The were by of a to the The was from the by the at by the for formation to studies W. Liu J. Jiang S. Lu M. 2000; PubMed Scopus Google Scholar, J.T. 13: PubMed Scopus Google Scholar). was at by a of in the range of the the were to and in the at for by of as The was and the of the was was to the formation the and as S. Jiang S. 2003; PubMed Scopus Google Scholar). an was with a or or sifuvirtide at a of 40 and at for The was at well with an of native was with of at for The was then with and with a of on the of sifuvirtide on the formation was by a as S. K. A.K. J. Virol. 1999; PubMed Scopus Google Scholar). a was with a in A or at was with and with at for The was then to the by at for and with a and the were at was an The by the peptides and the were as K. J. Med. PubMed Scopus Google Scholar). by unilamellar of were as S. W. B. Lu J. J. J. Wu S. Jiang S. J. Biol. Chem. 2007; Full Text Full Text PDF PubMed Scopus Google Scholar). 20 of was a of and to of The was by in of The was for 5 and then two an of sifuvirtide, or to was a high as S. W. B. Lu J. J. J. Wu S. Jiang S. J. Biol. Chem. 2007; Full Text Full Text PDF PubMed Scopus Google Scholar). were to of were into the a or only a The in by into without a were from the in the binding and were by of the peptides sifuvirtide, or in and were on a with an of and was from to at a of were by of the without was used for of HIV-1-mediated cell-cell fusion as S. Lu Liu S. A.K. PubMed Scopus (256) Google Scholar). In were with a and then with in at for h in the or of The and were an with an The of cell-cell fusion and the were as S. Lu Liu S. A.K. PubMed Scopus (256) Google Scholar). of of and of sifuvirtide on by various T20-resistant virus isolates and laboratory-adapted HIV-1 was as S. Lu Liu S. A.K. PubMed Scopus (256) Google Scholar). In were with HIV-1 isolates at in of in the or of sifuvirtide at the were and were without the of was from each with of and for by The of sifuvirtide against primary HIV-1 isolates was as S. Lu Liu S. A.K. PubMed Scopus (256) Google Scholar). the were from the of healthy a The were in and at for The were and at 5 in 5 of and of by at for The were with the primary HIV-1 isolates at a of of in the or of sifuvirtide at were The were and for by The of and were and Pharmacokinetic healthy were in studies. In the and of single dose a of 40 were to a single subcutaneous injection dose of sifuvirtide daily in dose These 5 20 and 40 was by adverse abdominal and and In the pharmacokinetic of single dose a of were to a subcutaneous injection once daily dose of 10, 20, and of sifuvirtide in were at the 30, 5 and and and h In the safety, tolerability, and pharmacokinetic of multiple dose a of multiple subcutaneous injection once daily of of sifuvirtide daily dose and were at the and and and h were at and h of sifuvirtide were by and of is derived from the gp41 CHR of HIV-1 on the three-dimensional of HIV-1 gp41 and sifuvirtide was to its and antiviral The that are for or were and were into the sifuvirtide to the formation of at the and of the conformation. was by to the hydrophobic a was to the of the peptide, because of this to the N-terminal of an is to its a of the the sifuvirtide is of in and and structure with the native CHR these sifuvirtide is different from in and from in of the structure of sifuvirtide, we have its in the or of the the of sifuvirtide, and show a at that these peptides have conformation. The for sifuvirtide is to that of and and is of with a J. Biol. 2000; PubMed Scopus Google Scholar). In the of sifuvirtide in the of a at and that the sifuvirtide and the formation of of peptides and also to the formation of by an with that of sifuvirtide of the a of for sifuvirtide and for in the of T20, on the other with demonstrated by the lack of at and The result that sifuvirtide to in a manner of by forming a which is in great to that of T20. We then the changes in of over from to to the binding of sifuvirtide to the of in with that of The are found to have a significantly of and more that of The of was that of was The of sifuvirtide and and of with of sifuvirtide are with of which is to the as well as binding to the However, structure with with S. Lu J. Wu S. Jiang S. J. Biol. Chem. 280: Full Text Full Text PDF PubMed Scopus Google Scholar). Unlike T20, to with a to the by and used it to the antiviral of HIV-1 fusion inhibitors S. Jiang S. 2003; PubMed Scopus Google Scholar, S. Lu J. Wu S. Jiang S. J. Biol. Chem. 280: Full Text Full Text PDF PubMed Scopus Google Scholar). In this was used to the sifuvirtide and and its potential in forming the in exhibited because it and and the sifuvirtide and each a in the of the sifuvirtide was to with by the of a to sifuvirtide or In such changes were found for with that and that of sifuvirtide or These are with from studies the sifuvirtide with we sifuvirtide can the formation of and in by S. K. A.K. J. Virol. 1999; PubMed Scopus Google Scholar). sifuvirtide and were to the formation of in a failed to In addition, sifuvirtide potency in disrupting the formation of by its of with of Unlike T20, with studies suggest that the CHR in the of the with the and in the formation of fusion W. Lu M. J. Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar). the in an we the from the of a or with in large was was into a T20. The binding of to was However, the of sifuvirtide and to were to the binding we used to the of the peptides with peptides the of the peptides with the of the was the was in the with in sifuvirtide and show These results suggest T20, sifuvirtide and with the target cell of on HIV-1-mediated and is to the sifuvirtide has anti-HIV we the of sifuvirtide on cell-cell in sifuvirtide could the fusion with an of In inhibited the fusion with an of sifuvirtide is more active in fusion of viral and cellular we sifuvirtide for its on HIV-1-mediated infection. sifuvirtide was also more to of We then sifuvirtide and with a of primary HIV-1 in sifuvirtide was highly active in primary HIV-1 isolates with genotypes and of on primary HIV-1 ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± in a new of T20-resistant HIV were in and anti-HIV sifuvirtide and T20, we to sifuvirtide is to of HIV-1 strains resistant to T20. and T20-resistant strains with well the resistance were used in D.C. J. 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We found that sifuvirtide and were active against but sifuvirtide was more T20, with laboratory-adapted and primary HIV-1 sifuvirtide showed against T20-resistant strains with from to failed to with at to These results suggest that sifuvirtide can used as an fusion inhibitor for treatment of patients with in those by T20-resistant of on T20-resistant or resistant to ± ± ± ± ± ± ± ± ± ± or resistant to T20. in a new and Pharmacokinetic of was from Phase Ia studies to adverse or The were in in the of single dose of sifuvirtide, including injection in of in and of in and of in the were and without In a pharmacokinetic of a single dose of sifuvirtide, was also in one and of in one the of single dose administration of of The process showed a in was 20.0 ± 8.6 h and was anti-HIV in of pharmacokinetic injection of different of in healthy h ± ± ± subcutaneous h ± ± ± subcutaneous h ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± subcutaneous ± subcutaneous ± ± ± subcutaneous in a new and studies of multiple of sifuvirtide were in with subcutaneous injection of of sifuvirtide once daily for an injection an of a transient of and These adverse were to the The of sifuvirtide was ± and was ± 7.9 h and these are with those of single dose Therefore, this dose in administration was and a of as well of pharmacokinetic and of injection of dose dose h ± ± h ± ± h ± ± ± ± ± ± ± ± ± single ± ± single ± single single in a new In the we have designed a novel anti-HIV based on the and of HIV-1 The sifuvirtide was to its demonstrated that sifuvirtide have a different mechanism of action from T20. Unlike T20, sifuvirtide could structure with and more against HIV-1 isolates with genotypes and phenotypes. In sifuvirtide was also highly effective against T20-resistant strains. clinical Phase Ia studies demonstrated that sifuvirtide has good safety, tolerability, and pharmacokinetic its potential as an effective fusion inhibitor for treatment of studies that peptides derived from the NHR and CHR of HIV-1 gp41 have antiviral (15Liu S. Wu S. Jiang S. Curr. Pharm. Des. 2007; 13: 143-162Crossref PubMed Scopus (122) Google Scholar, 17Debnath A.K. Expert. Opin. Investig. Drugs. 2006; 15: 465-478Crossref PubMed Scopus (17) Google Scholar). For two and T20, are most active inhibitors on HIV-1-mediated cell-cell fusion and infection. these two peptides are by the at its that is for its anti-HIV S. W. B. Lu J. J. J. Wu S. Jiang S. J. Biol. Chem. 2007; Full Text Full Text PDF PubMed Scopus Google Scholar, D.C. Kim P.S. Cell. 1998; Full Text Full Text PDF PubMed Scopus Google Scholar, D.C. 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Engl. 2002; PubMed Google a in which and were to that the and of the anti-HIV the In we into the sifuvirtide to its and its and antiviral potency The by sifuvirtide and its NHR with a of as by In the by which is as a core structure of the has a of Therefore, sifuvirtide target the NHR with a also suggest that sifuvirtide have different mechanism of action from T20. sifuvirtide was designed to the gp41 this sifuvirtide could a highly in the of but sifuvirtide, T20, with the demonstrated high against a wide of primary isolates with different genotypes and phenotypes. sifuvirtide is designed on the of the gp41 of HIV-1 it also on such as as in that the target of sifuvirtide is to in gp41 from that sifuvirtide is to more effective against T20. is known that R5 in most patients by with the of HIV, by of or virus, which for of the (8Berger E.A. Murphy P.M. Farber J.M. Annu. Rev. Immunol. 1999; 17: 657-700Crossref PubMed Scopus (1865) Google Scholar, J.P. J.A. AIDS PubMed Scopus Google Scholar). Therefore, sifuvirtide active for a in clinical T20, the first HIV-1 inhibitor approved for the treatment of HIV-1 in patients (4Este J.A. Telenti A. Lancet. 2007; 370: 81-88Abstract Full Text Full Text PDF PubMed Scopus (242) Google has it outside and targets the of virus, Therefore, it is to have with those or targeting cellular However, it has more subcutaneous mg) and daily of result in the injection and for HIV/AIDS In sifuvirtide in potency and of sifuvirtide in sifuvirtide to with clinical and of which the injection and of the has a in antiretroviral drug combinations, it also has the of drug resistance (4Este J.A. Telenti A. Lancet. 2007; 370: 81-88Abstract Full Text Full Text PDF PubMed Scopus (242) Google Scholar). is highly effective against T20-resistant strains Therefore, sifuvirtide used to patients with T20-resistant We that sifuvirtide is an ideal fusion inhibitor with potency, and resistance that can used for the treatment of HIV/AIDS patients, including those are by HIV-1 strains resistant to T20. of anti-HIV inhibitors are in classes of anti-HIV such as inhibitors and inhibitors against have showed great promise in HIV in (4Este J.A. Telenti A. Lancet. 2007; 370: 81-88Abstract Full Text Full Text PDF PubMed Scopus (242) Google Scholar, 5Moore J.P. Doms R.W. Proc. Natl. Acad. Sci. U. S. A. 2003; 100: 10598-10602Crossref PubMed Scopus (256) Google Scholar, J.P. M. Rev. Cell. Biol. 2000; PubMed Scopus Google Scholar). These novel drugs have demonstrated in vitro with other classes of the for in In addition, efforts have also been made to develop novel against viral targets such as viral fusion viral and In with novel drugs against viral target such as viral fusion sifuvirtide was designed and in vitro and in on results far, we that sifuvirtide has that of In its against T20-resistant strains suggest that sifuvirtide to a in the patients have T20-resistant The in of sifuvirtide in HIV-1 in patients is being in Phase clinical