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Rational improvement of gp41-targeting HIV-1 fusion inhibitors: an innovatively designed Ile-Asp-Leu tail with alternative conformations

View Article: PubMed Central - PubMed

ABSTRACT

Peptides derived from the C-terminal heptad repeat (CHR) of HIV gp41 have been developed as effective fusion inhibitors against HIV-1, but facing the challenges of enhancing potency and stability. Here, we report a rationally designed novel HIV-1 fusion inhibitor derived from CHR-derived peptide (Trp628~Gln653, named CP), but with an innovative Ile-Asp-Leu tail (IDL) that dramatically increased the inhibitory activity by up to 100 folds. We also determined the crystal structures of artificial fusion peptides N36- and N43-L6-CP-IDL. Although the overall structures of both fusion peptides share the canonical six-helix bundle (6-HB) configuration, their IDL tails adopt two different conformations: a one-turn helix with the N36, and a hook-like structure with the longer N43. Structural comparison showed that the hook-like IDL tail possesses a larger interaction interface with NHR than the helical one. Further molecular dynamics simulations of the two 6-HBs and isolated CP-IDL peptides suggested that hook-like form of IDL tail can be stabilized by its binding to NHR trimer. Therefore, CP-IDL has potential for further development as a new HIV fusion inhibitor, and this strategy could be widely used in developing artificial fusion inhibitors against HIV and other enveloped viruses.

No MeSH data available.


Related in: MedlinePlus

HIV-1 gp41 CHR-derived peptides and their inhibition activities.(A) Schematic illustration of HIV-1 gp41 functional regions and NHR- or CHR-derived peptide sequences. The residue numbers of each region correspond to their positions in gp160 of HIV-1HXB2. FP, fusion peptide; CP, cytoplasmic peptide. The MT hook residues in the N terminus of CHR are marked in green. The IDL hook residues in the C terminus are marked in red. (B) Inhibition activities of CP-IDL, CP-SM, CP-SW, CP and T-20 to HIV-1 clinical strain 92UG029 infecting M7 cells. (C) Inhibition of CP-IDL, CP-SM, CP-SW, CP and T-20 to HIV-1 clinical strain 92UG024 infecting M7 cells.
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f1: HIV-1 gp41 CHR-derived peptides and their inhibition activities.(A) Schematic illustration of HIV-1 gp41 functional regions and NHR- or CHR-derived peptide sequences. The residue numbers of each region correspond to their positions in gp160 of HIV-1HXB2. FP, fusion peptide; CP, cytoplasmic peptide. The MT hook residues in the N terminus of CHR are marked in green. The IDL hook residues in the C terminus are marked in red. (B) Inhibition activities of CP-IDL, CP-SM, CP-SW, CP and T-20 to HIV-1 clinical strain 92UG029 infecting M7 cells. (C) Inhibition of CP-IDL, CP-SM, CP-SW, CP and T-20 to HIV-1 clinical strain 92UG024 infecting M7 cells.

Mentions: Inspired by the gp41-derived MT hook, we aimed to append a rationally designed artificial tail to the C-terminus of HIV-1 fusion inhibitors to enhance their antiviral potency. Finally, by introducing an innovative C-terminal tail of Ile-Asp-Leu (IDL), we succeeded to increase the anti-HIV potency of a CHR-derived peptide (Trp628~Gln653, named CP, Fig. 1A) by more than 100-fold. Unexpectedly, the crystal structures of CP-IDL in complex with NHR helices at different lengths (N36: Ser546~Leu581, and N43: Val539~Leu581, Fig. 1A) show that IDL tail is capable to bear two different conformations: a part of an α-helix (with N36) or a hook-like structure (with N43). Further structural analysis and molecular dynamic (MD) simulations suggested that the alternative conformations of IDL tail allow the enhancement of the anti-HIV potency of CP-IDL peptide. Based on the present study, we believe that similar approaches are possible to be adopted in the improvement of CHR-derived fusion inhibitors against other viruses.


Rational improvement of gp41-targeting HIV-1 fusion inhibitors: an innovatively designed Ile-Asp-Leu tail with alternative conformations
HIV-1 gp41 CHR-derived peptides and their inhibition activities.(A) Schematic illustration of HIV-1 gp41 functional regions and NHR- or CHR-derived peptide sequences. The residue numbers of each region correspond to their positions in gp160 of HIV-1HXB2. FP, fusion peptide; CP, cytoplasmic peptide. The MT hook residues in the N terminus of CHR are marked in green. The IDL hook residues in the C terminus are marked in red. (B) Inhibition activities of CP-IDL, CP-SM, CP-SW, CP and T-20 to HIV-1 clinical strain 92UG029 infecting M7 cells. (C) Inhibition of CP-IDL, CP-SM, CP-SW, CP and T-20 to HIV-1 clinical strain 92UG024 infecting M7 cells.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC5036048&req=5

f1: HIV-1 gp41 CHR-derived peptides and their inhibition activities.(A) Schematic illustration of HIV-1 gp41 functional regions and NHR- or CHR-derived peptide sequences. The residue numbers of each region correspond to their positions in gp160 of HIV-1HXB2. FP, fusion peptide; CP, cytoplasmic peptide. The MT hook residues in the N terminus of CHR are marked in green. The IDL hook residues in the C terminus are marked in red. (B) Inhibition activities of CP-IDL, CP-SM, CP-SW, CP and T-20 to HIV-1 clinical strain 92UG029 infecting M7 cells. (C) Inhibition of CP-IDL, CP-SM, CP-SW, CP and T-20 to HIV-1 clinical strain 92UG024 infecting M7 cells.
Mentions: Inspired by the gp41-derived MT hook, we aimed to append a rationally designed artificial tail to the C-terminus of HIV-1 fusion inhibitors to enhance their antiviral potency. Finally, by introducing an innovative C-terminal tail of Ile-Asp-Leu (IDL), we succeeded to increase the anti-HIV potency of a CHR-derived peptide (Trp628~Gln653, named CP, Fig. 1A) by more than 100-fold. Unexpectedly, the crystal structures of CP-IDL in complex with NHR helices at different lengths (N36: Ser546~Leu581, and N43: Val539~Leu581, Fig. 1A) show that IDL tail is capable to bear two different conformations: a part of an α-helix (with N36) or a hook-like structure (with N43). Further structural analysis and molecular dynamic (MD) simulations suggested that the alternative conformations of IDL tail allow the enhancement of the anti-HIV potency of CP-IDL peptide. Based on the present study, we believe that similar approaches are possible to be adopted in the improvement of CHR-derived fusion inhibitors against other viruses.

View Article: PubMed Central - PubMed

ABSTRACT

Peptides derived from the C-terminal heptad repeat (CHR) of HIV gp41 have been developed as effective fusion inhibitors against HIV-1, but facing the challenges of enhancing potency and stability. Here, we report a rationally designed novel HIV-1 fusion inhibitor derived from CHR-derived peptide (Trp628~Gln653, named CP), but with an innovative Ile-Asp-Leu tail (IDL) that dramatically increased the inhibitory activity by up to 100 folds. We also determined the crystal structures of artificial fusion peptides N36- and N43-L6-CP-IDL. Although the overall structures of both fusion peptides share the canonical six-helix bundle (6-HB) configuration, their IDL tails adopt two different conformations: a one-turn helix with the N36, and a hook-like structure with the longer N43. Structural comparison showed that the hook-like IDL tail possesses a larger interaction interface with NHR than the helical one. Further molecular dynamics simulations of the two 6-HBs and isolated CP-IDL peptides suggested that hook-like form of IDL tail can be stabilized by its binding to NHR trimer. Therefore, CP-IDL has potential for further development as a new HIV fusion inhibitor, and this strategy could be widely used in developing artificial fusion inhibitors against HIV and other enveloped viruses.

No MeSH data available.


Related in: MedlinePlus