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Lipopeptide inhibitors of HIV-1

A lipophilic, fatty acid-based technology applied in the field of HIV-1 lipopeptide inhibitors

Inactive Publication Date: 2012-04-25
YEDA RES & DEV CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Another disadvantage associated with synthetic peptides has to do with solubility and stability in water-based pharmaceutically acceptable carriers, such as with the process of producing injectable solution formulations of HIV fusion inhibitor peptides

Method used

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  • Lipopeptide inhibitors of HIV-1
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  • Lipopeptide inhibitors of HIV-1

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0197] Example 1: Anchoring of N36 to membranes enhances its inhibitory activity:

[0198] To carefully study the role of N36 anchoring to the membrane, we conjugated octanoic acid, dodecanoic acid and palmitic acid to the N-terminus of N36 (Table 1). The resulting peptides C8-N36, C12-N36 and C16-N36 (Table 1) were examined in a cell-cell fusion inhibition assay and the results are shown in figure 1 middle. A correlation was observed between the length of the conjugated fatty acid and the inhibitory activity of the N-conjugated N36 peptide. N36, C8-N36, C12-N36 and C16-N36 exhibited ICs of 488±119nM, 222±56nM, 190±21nM and 72±27nM, respectively 50 value. Interestingly, AcN36 was not active up to 2000 nM; we therefore considered it to be inactive. This compares with ICs of 16000 ± 2000 nM and 584 ± 46 nM indicating the acetylated and non-acetylated forms of N36 50 This is related to previous studies of (Bewley et al., 2002, J. Biol. Chem. 277: 14238-45). Taken together, ...

Embodiment 2

[0201] Example 2: The orientation of anchored N36 to the endogenous CHR region is not critical:

[0202] To examine the importance of proper orientation of the N36 peptide in relation to the prefusion conformation, we also conjugated octanoic, dodecanoic and palmitic acids to the C-terminus of a modified N36, termed N36M (Table 1). The parental peptides and the resulting fatty acid conjugated peptides N36M, N36M-C8, N36M-C12, and N36M-C16 were examined in a cell-cell fusion inhibition assay (Table 1), and the results are in figure 1 available in . Likewise, a correlation was observed between conjugated fatty acid length and C-conjugated N36 peptide. N36M, N36M-C8, N36M-C12 and N36M-C16 exhibited IC50 values ​​of 531±48nM, 354±25nM, 241±89nM and 159±47nM, respectively. Since acetylation of N36 abolishes its activity, we added acetyl groups to N36M-C12 and N36M-C16 to obtain AcN36M-C12 and AcN36M-C16. These two lipopeptides were examined in a cell-cell fusion inhibition assay...

Embodiment 3

[0204] Example 3: Analysis of Inhibition Curves Shows Different Modes of Inhibition for the Peptides of the Invention:

[0205] Figure 3 presents a representative experiment showing the inhibitory activity curves of N36 and its N-terminal fatty acid conjugated analogs. Figure 3 shows the different shapes of the binding curves of different peptides from S-shaped through intermediate shapes to hyperbolic. The S-shape can be explained by the oligomerization propensity of N36. Therefore, without wishing to be bound by theory or mechanism of action, we speculate that the different binding profiles may be due to different inhibitory oligomeric states of the peptides. Therefore, for the best fit, we applied the equation containing the synergy parameter, in this case indicative of the inhibitory oligomeric state of the peptide. Therefore, after the fit is achieved, the c value represents the oligomeric state of the peptide. Figure 4 Values ​​of oligomerization parameters for diffe...

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Abstract

The invention provides lipophilic conjugates comprising a short isolated peptide coupled to a hydrophobic moiety, the peptide comprising a sequence derived from the HIV-1 gp41 N-terminal heptad repeat domain, said peptide after conjugation to the hydrophobic moiety possesses anti-fusogenic activity higher than prior to conjugation. The lipophilic conjugates are suitable for treatment of infections caused by human and non-human retroviruses, especially HIV.

Description

technical field [0001] The present invention relates to lipophilic conjugates comprising a hydrophobic moiety coupled to a peptide derived from the N-terminal heptad repeat domain of HIV-1 gp41, the present invention relates to comprising such lipophilic conjugates The pharmaceutical composition of , and the use of the pharmaceutical composition as an inhibitor of the transmission of human and non-human retroviruses, especially HIV, to uninfected cells. Background technique [0002] HIV-1, like other enveloped viruses, utilizes proteins embedded in its membrane called "envelope proteins" to facilitate the fusion process. The envelope protein includes two non-covalently linked subunits: gp120 and gp41, which are organized as trimers. gp120 is responsible for host tropism (Clapham, P.R. and McKnigh, A. 2002, J. Gen. Virol., 83; 1809-29), while the transmembrane subunit gp41 is responsible for the actual fusion event (Chan, D.C. and Kim, P.S., 1998 , Cell, 93; 681-4). The ex...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K47/48C07K14/16A61K49/00A61P31/18
CPCA61K49/0017A61K47/48038C12N2740/16122A61K47/48123C07K14/005A61K47/48107A61K47/542A61K47/551A61K47/554A61P31/14A61P31/18
Inventor 耶切尔·沙伊耶尔·韦克斯勒-科恩
Owner YEDA RES & DEV CO LTD
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