Peptides for inhibition of HIV infection

Details Peptides for inhibition of HIV infection Peptides for inhibition of HIV infection

2001-04-16

2002-12-03

Park, Hankyel T. (Department: 1648)

Chemistry: natural resins or derivatives; peptides or proteins;

Proteins, i.e., more than 100 amino acid residues

Blood proteins or globulins, e.g., proteoglycans, platelet...

C530S324000

Reexamination Certificate

active

06489449

ABSTRACT:

BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to peptides that can inhibit the infection of HIV, and more particularly, to peptides consisting of less than 30 amino acids which can introduce a helix capping motif into a peptide derived from C-terminal helical region (its 628-646
th
amino acid region) of gp41, an envelope glycoprotein of HIV, as well as consisting of the symmetrical bivalent peptide through the introduction of a branched amino acid, Fmoc-Lys(Fmoc)-OH at C-terminus of its peptide, and induce a more stable helical structure thus inhibiting the infection of HIV.
2. Description of the Related Art
Host cell infection by HIV is mediated by the binding between envelope glycoproteins of HIV and receptors of a host cell such as CD4 and chemokine receptors (Berger, AIDS, 11, S3-16, 1997; Doranz et al., Immunol. Res., 16, 15-28, 1997; Moore et al., Current Opin. Immunol., 9, 551-562, 1997). When gp120 of HIV binds CD4 of a host cell, gp120 undergoes a structural change so that it can bind a chemokine receptor in a host cell. Once the binding is completed, a hydrophobic amino terminal fusion peptide region of gp41 of HIV can be inserted in the membrane of a host cell. Then, three gp41 envelope glycoproteins form a six-stranded a-helical bundle, in which three N-peptides associate to form the central trimeric coiled-coil and three C-peptides pack obliquely in an antiparalllel manner on the surface of the coiled-coil core. This bundle structure is involved in a fusion between HIV cell membrane and a host cell membrane as a result thus enabling the core of HIV to penetrate into the cytoplasm of a host cell (Chan and Kim, Cell, 93, 681-684, 1998). Gp41, a glycoprotein present on the envelope of HIV, is also involved in the fusion between HIV envelope and human cell membrane. Gp41 consists of a fusion peptide which exhibits an activity on cell membrane fusion, an N-terminal helical region, a C-terminal helical region, a transmembrane region, and a cytoplasmic region. Peptides derived from N- and C-helical region of the extracellular domain of gp41 can bind to each other in an aqueous solution due to their strong interactions and thus form a very stable complex consisting of six helices from three N-peptides and three C-peptides. The above interaction between the two helical regions is known to play a crucial role in the activity of cell fusion as well as the structural stability of gp41 protein itself. Therefore, it becomes obvious form the above that any substance that can inhibit the above interaction between the two helical regions will be able to inhibit the stability as well as the function of gp41, which will eventually lead to the inhibition of HIV infection thus becoming a promising therapeutic agent for AIDS treatment. In particular, hydrophobic interactions among three nonpolar residues (Trp
628
, Trp
631
, and IIe
635
of gp41) of C34 peptide (the 628
th
-661
st
amino acid) derived from C-terminus of gp41 and a cavity formed by C-terminal portion of the coiled-coil core are known to be important in antiviral activities. These structural features imply that the formation of a helical structure is a prerequisite for the binding between a C-peptide and an N-terminal helical region. DP178, a 36-mer peptide(638
th
-673
rd
amino acid, SEQ ID NO.1: YTSLIHSLIEESQNQQEKNEQELLELDKWASLWNWF) derived from C-terminal helical region of gp41 is also known to inhibit gp41-mediated cell fusion, and 1 ng/mL of DP178 has about 90% inhibitory activity on cell fusion mediated by gp41. DP178 is known to inhibit cell fusion by binding an N-terminal helical region of gp4l thus preventing its interaction with the C-terminal helical region of gp41. DP178 and its modified peptides having an antiviral activity consisted of at least 34-36 amino acids and they did not form a secondary structure in an aqueous solution. However, when the i
th
and the (i+7)
th
amino acid residues of a peptide consisting of 27 amino acids derived from C-terminus of gp41 without an antiviral activity are chemically cross-linked, the above peptide formed a helical structure and showed an antiviral activity. Hence, helical stabilization of the C-peptides appears to be an important factor in promoting binding affinity for the coiled-coil motif of gp41 as well as for anti-HIV activity(Judice, Proc. Natl. Acd. Sci. USA, 94,13426-13430, 1997).
However, thus obtained peptides have drawbacks as specified below. First, a peptide should have at least 30 amino acids to be able to inhibit gp41-mediated cell fusion and this incurs a lot of expense in synthesizing those peptides. Second, there requires an additional method to chemically link amino acid residues in order to obtain a peptide with a helical structure or a bivalent sequence. Therefore, it has been a long-felt need to develop a peptide with an antiviral activity which consists of relatively less amino acids compared to traditional peptides which have more than 36 amino acids and forms a stable helical structure in an aqueous solution without necessitating complicated post-synthetic modifications.
SUMMARY OF THE INVENTION
To solve the above problems, the inventors of the present invention introduced a helix-capping motif into both N-terminus and C-terminus of a peptide derived from a C-terminal helical region of gp41 or substituted into amino acids that can facilitate the formation of a helical structure in order to stabilize a helical structure of a peptide and subsequently confirmed that the peptides can inhibit the cell fusion of HIV via a strong interaction with N-terminal helical region of gp41. The object of the present invention is to provide peptides that can inhibit the infection of HIV containing helix-capping motifs at both ends of a 19-mer peptide (628
th
-646
th
region) derived from C-terminus of gp41, an envelope glycoprotein of HIV.


REFERENCES:
Berger, HIV entry and tropism: the chemokine receptor connection, AIDS 11(suppl A):S3-S16 (1997).
Doranz et al., Chemokine receptors as fusion cofactors for human immunodeficiency virus type 1 (HIV-1), Immunologic Research 16:15-28 (1997).
Moore et al., Co-receptors for HIV-1 entry, Current Opinion in Immunology 9(4):551-562 (1997).
Chan et al., HIV entry and its inhibition, Cell, 93:681-684 (1998).
Judice et al., Inhibition of HIV type 1 in infectivity by constrained &agr;-helical peptides: implications for the viral fusion mechanism, Prop. Natl. Acad. Sci. USA 94:13426-13430 (1997).
Ryu et al., Development for an in vitro assay system for screening of gp41 inhibitory compounds, Molecules and Cells 8(6):717-723 (1998).
Woo et al., Inhibition of gp 120-CD4 interaction by various plant extracts, Phytomedicine 4:53-58 (1997).
Lawless et al., HIV-1 Membrane Fusion Mechanism: Structural Studies of the Interactions Between Biologically-active Peptides from gp41, Biochemistry 35:13697-13708, at 13705 (1996).
Rimsky et al., Determinants of Human Immunodeficiency Virus Type 1 Resistance to gp41-Derived Inhibitory Peptides, Journal of Virology 72:986-993 (1998).
Wild et al., Peptides Corresponding to Predictive &agr;-Helical Domain of Human Immunodeficiency Virus Type 1 gp41 are Potent Inhibitors of Virus Infection, PNAS 91:9770-9774 (1994).

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