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Biophysical property and broad anti-HIV activity of albuvirtide, a 3-maleimimidopropionic acid-modified peptide fusion inhibitor.

Chong H, Yao X, Zhang C, Cai L, Cui S, Wang Y, He Y - PLoS ONE (2012)

Bottom Line: The results showed that ABT had potent inhibitory activity against the subtypes A, B and C that predominate the worldwide AIDS epidemics, and subtype B', CRF07_BC and CRF01_AE recombinants that are currently circulating in China.Furthermore, ABT was also highly effective against HIV-1 variants resistant to T20.Taken together, our data indicate that the chemically modified peptide ABT can serve as an ideal HIV-1 fusion inhibitor.

View Article: PubMed Central - PubMed

Affiliation: Institute of Pathogen Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.

ABSTRACT
Albuvirtide (ABT) is a 3-maleimimidopropionic acid (MPA)-modified peptide HIV fusion inhibitor that can irreversibly conjugate to serum albumin. Previous studies demonstrated its in vivo long half-life and potent anti-HIV activity. Here, we focused to characterize its biophysical properties and evaluate its antiviral spectrum. In contrast to T20 (Enfuvirtide, Fuzeon), ABT was able to form a stable α-helical conformation with the target sequence and block the fusion-active six-helix bundle (6-HB) formation in a dominant-negative manner. It efficiently inhibited HIV-1 Env-mediated cell membrane fusion and virus entry. A large panel of 42 HIV-1 pseudoviruses with different genotypes were constructed and used for the antiviral evaluation. The results showed that ABT had potent inhibitory activity against the subtypes A, B and C that predominate the worldwide AIDS epidemics, and subtype B', CRF07_BC and CRF01_AE recombinants that are currently circulating in China. Furthermore, ABT was also highly effective against HIV-1 variants resistant to T20. Taken together, our data indicate that the chemically modified peptide ABT can serve as an ideal HIV-1 fusion inhibitor.

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Related in: MedlinePlus

Inhibition of ABT on 6-HB formation and cell membrane fusion.A. ABT and C34 can efficiently inhibit 6-HB formation in a dose-dependent manner, but T20 has no such effect. B. Inhibition of HIV-1HXB2 Env-mediated cell-cell membrane fusion by ABT, C34 and T20. The data were derived from the results of three independent experiments and are expressed as means ± standard deviations.
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pone-0032599-g004: Inhibition of ABT on 6-HB formation and cell membrane fusion.A. ABT and C34 can efficiently inhibit 6-HB formation in a dose-dependent manner, but T20 has no such effect. B. Inhibition of HIV-1HXB2 Env-mediated cell-cell membrane fusion by ABT, C34 and T20. The data were derived from the results of three independent experiments and are expressed as means ± standard deviations.

Mentions: To elucidate the mechanism of action of ABT, we checked whether ABT can physically block the formation of 6-HB as modeled by the N36 and C34 peptides described previously [16], [26]. As shown in Fig. 4A, both ABT and C34 were able to inhibit the formation of 6-HB in a dose-dependent fashion, but the former exhibited significantly higher potency than C34 as manifested by its IC50 value of 0.82 µM compared with 3.25 µM of C34. Unlike ABT and C34, T20 had no such effect at a concentration as high as 20 µM. These results were consistent with our observations from CD studies and demonstrated that ABT acts in a mechanism of blocking 6-HB formation in a dominant-negative manner. Further, we examined the inhibitory activity of ABT on HIV-1HXB2 Env-mediated cell-cell membrane fusion. As shown in Fig. 4B, ABT could inhibit the fusion with an IC50 of 1.27 nM, while C34 and T20 inhibited the fusion with IC50 values of 3.86 nM and 56.22 nM, respectively.


Biophysical property and broad anti-HIV activity of albuvirtide, a 3-maleimimidopropionic acid-modified peptide fusion inhibitor.

Chong H, Yao X, Zhang C, Cai L, Cui S, Wang Y, He Y - PLoS ONE (2012)

Inhibition of ABT on 6-HB formation and cell membrane fusion.A. ABT and C34 can efficiently inhibit 6-HB formation in a dose-dependent manner, but T20 has no such effect. B. Inhibition of HIV-1HXB2 Env-mediated cell-cell membrane fusion by ABT, C34 and T20. The data were derived from the results of three independent experiments and are expressed as means ± standard deviations.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3293837&req=5

pone-0032599-g004: Inhibition of ABT on 6-HB formation and cell membrane fusion.A. ABT and C34 can efficiently inhibit 6-HB formation in a dose-dependent manner, but T20 has no such effect. B. Inhibition of HIV-1HXB2 Env-mediated cell-cell membrane fusion by ABT, C34 and T20. The data were derived from the results of three independent experiments and are expressed as means ± standard deviations.
Mentions: To elucidate the mechanism of action of ABT, we checked whether ABT can physically block the formation of 6-HB as modeled by the N36 and C34 peptides described previously [16], [26]. As shown in Fig. 4A, both ABT and C34 were able to inhibit the formation of 6-HB in a dose-dependent fashion, but the former exhibited significantly higher potency than C34 as manifested by its IC50 value of 0.82 µM compared with 3.25 µM of C34. Unlike ABT and C34, T20 had no such effect at a concentration as high as 20 µM. These results were consistent with our observations from CD studies and demonstrated that ABT acts in a mechanism of blocking 6-HB formation in a dominant-negative manner. Further, we examined the inhibitory activity of ABT on HIV-1HXB2 Env-mediated cell-cell membrane fusion. As shown in Fig. 4B, ABT could inhibit the fusion with an IC50 of 1.27 nM, while C34 and T20 inhibited the fusion with IC50 values of 3.86 nM and 56.22 nM, respectively.

Bottom Line: The results showed that ABT had potent inhibitory activity against the subtypes A, B and C that predominate the worldwide AIDS epidemics, and subtype B', CRF07_BC and CRF01_AE recombinants that are currently circulating in China.Furthermore, ABT was also highly effective against HIV-1 variants resistant to T20.Taken together, our data indicate that the chemically modified peptide ABT can serve as an ideal HIV-1 fusion inhibitor.

View Article: PubMed Central - PubMed

Affiliation: Institute of Pathogen Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.

ABSTRACT
Albuvirtide (ABT) is a 3-maleimimidopropionic acid (MPA)-modified peptide HIV fusion inhibitor that can irreversibly conjugate to serum albumin. Previous studies demonstrated its in vivo long half-life and potent anti-HIV activity. Here, we focused to characterize its biophysical properties and evaluate its antiviral spectrum. In contrast to T20 (Enfuvirtide, Fuzeon), ABT was able to form a stable α-helical conformation with the target sequence and block the fusion-active six-helix bundle (6-HB) formation in a dominant-negative manner. It efficiently inhibited HIV-1 Env-mediated cell membrane fusion and virus entry. A large panel of 42 HIV-1 pseudoviruses with different genotypes were constructed and used for the antiviral evaluation. The results showed that ABT had potent inhibitory activity against the subtypes A, B and C that predominate the worldwide AIDS epidemics, and subtype B', CRF07_BC and CRF01_AE recombinants that are currently circulating in China. Furthermore, ABT was also highly effective against HIV-1 variants resistant to T20. Taken together, our data indicate that the chemically modified peptide ABT can serve as an ideal HIV-1 fusion inhibitor.

Show MeSH
Related in: MedlinePlus