Chemokine-derived synthetic peptides

Details Chemokine-derived synthetic peptides Chemokine-derived synthetic peptides

2000-04-06

2003-09-02

Housel, James (Department: 1648)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Peptide containing doai

C424S085100, C435S069100, C530S300000, C530S324000, C530S333000, C530S351000

Reexamination Certificate

active

06613742

ABSTRACT:

FIELD OF THE INVENTION
The invention relates to the field of synthetic peptides derived from chemokines. In particular, the invention relates to antiviral agents useful for inhibiting the infectivity of human acquired immunodeficiency virus. More particularly, the present invention is directed to synthetic peptides capable of inhibiting HIV-1 infection.
BACKGROUND OF THE INVENTION
Chemoattractant cytokines or “chemokines” are a group of proteins characterized by a fairly high degree of amino acid sequence conservation. They are chemoattractants for leukocytes. The chemotactic effect of substances on leukocytes may be determined by devices such as the chemotaxis chamber invented by Boyden (Boyden,
J. Ex. Med
. 115:453-66, 1962).
Chemokines act on responsive leukocytes subsets through chemokine receptors. Engagement of chemokine receptors results ultimately in the movement of the cell. Chemokine receptors belong to the superfamily of G-protein coupled receptors (GPCR) that possess seven transmembrane helices (Murphy, P. M.,
Annu. Rev. Immunol
. 12:593-633, (1994). The three-dimensional structure of chemokine receptors is not known since currently no crystal structure is available for any of GPCR proteins (Strader et al.,
Annu. Rev. Biochem
. 63:101-32, (1994); Kobilka, B.,
Annu. Rev. Neurosci
15:87-114, (1992)).
Chemokines are the natural ligands for chemokine receptors and are 8-10 kDa molecules which act as chemoattractants by signaling through their receptors and activating the target cells (Premack et al.,
Nature Medicine
2:1174-8, (1996)). Chemokines may be divided into at least three structural branches: C, CC, and CXC, according to variations in a shared cysteine motif (Schall,
Curr. Opin. Immunol
. 6:865-873,1994). The CX, also known as a, and the CC, also known as &bgr;, are the major classes of chemokines. Most CXC chemokines (those that contain an ELR sequence N-terminal to the CXC motif) are chemoattractants for neutrophils but not monocytes, whereas CC chemokines generally attract monocytes and lymphocytes, but not neutrophils. Basophils and eosinophils are affected predominantly by CC chemokines. The C chemokines appear to be lymphocyte specific.
Stromal-cell-derived factor-1 (SDF-1) is a member of the CXC chemokine family and is the ligand for CXC chemokine receptor 4 (CXCR4) (Tashiro et al.,
Science
261:600-603, (1993); Shirozu et al.,
Genomics
28:495-500, (1995)). The CC chemokines MIP-1&bgr; (macrophage inflammatory protein 1&bgr;), MIP-1a (macrophage inflammatory protein 1a) and RANTES (regulated on activation normal T cell expressed and secreted) bind CCR5.
Human immunodeficiency virus type 1 (HIV-1) enters cells through a fusion process in which the HIV-1 envelope glycoprotein gp 120 binds to CD4, the main receptor for HIV-1 on the cell surface. However, it has been known that CD4 alone is not sufficient for HIV-1 fusion and entry and that additional receptors may be needed (Maddon et al.,
Cell
47:333-348, (1986); Clapham et al.,
Virology
181:703-15, (1991)).
The chemokine receptors CXCR4 and CCR5 have been shown to be the long-sought coreceptors for non-syncytium-inducing and syncytium-inducing HIV-1 strains, respectively (Feng et al.,
Science
272:872-877, (1996); Deng et al.,
Nature
381:661-666, (1996); Dragic et al.,
Nature
381:667-673, (1996); Alkhatib et al.,
Science
272:1955-8, (1996)). While all HIV-1 strains appear to require either CXCR4, CCR5 or both (Zhang et al.,
Nature
383:768, (1996); Simmons et al.,
Journal of Virology
70:8355-60, (1996)), some strains can also use other chemokine receptors CCR3 and CCR2b as coreceptors for fusion and infection (Doranz et al.,
Cell
85:1149-58, (1996); Choe et al.,
Cell
85:1135-48, (1996)).
SDF-1 and CXCR4 play a role in HIV-1 viral entry. The fusion process may involve the initial binding of HIV-1 gp 120 to its high-affinity receptor CD4 which results in conformational changes in gp 120 and possibly also CD4 (Gershoni et al.,
Journal
7:1185-7, (1993); Clements et al.,
AIDS Research & Human Retroviruses
7:3-16. (1991); Sattentau et al.,
Journal of Virology
67:7383-93, (1993)). The gp 120-CD4 complex interacts with CXCR4 or other chemokine coreceptors to form a heterotrimeric complex of gp 120-CD4-coreceptor (Lapham et al.,
Science
274:602-5, (1996); Wu et al.,
Nature
6605:179-83, (1996); Trkola et al.,
Nature
384:184-7, (1996)). It has been shown that the HIV envelope can bind CXCR4 independently and that this interaction is enhanced by the presence of CD4 (Bandres et al.,
Journal of Virology
72:2500-2504, (1998).
On the other hand, it is also known that the CXCR4 ligand, SDF-1 inhibits HIV-1 infection (Bleul et al.,
Nature
382:829-833, (1996); Oberlin et al.,
Nature
382:833-835, (1996)).
Several inhibitors of HIV-1 have been found to target the coreceptor CXCR4 (Murakami et al.,
J. Exp. Med
. 186:1389-133, (1997); Schols et al.,
J. Exp. Med
. 186:1383-1388, (1997); Donzella et al.,
Nature Medicine
4:72-77, (1998); Doranz et al.,
J. Exp. Med
. 186:1395-1400, (1997)). Synthetic peptides derived from SDF-1 have been shown to posses anti-HIV activity (Heveker etal.,
Current Biology
8:369-376 (1998)). While the solution structure of SDF-1 has been determined (Crump et al.,
EMBO J
. 16:6996-7007 (1998)), there is no crystal structure available for CXCR4 to facilitate design of further inhibitors of HIV-1 binding to CXCR4.
There is a need for antiviral agents which can block HIV-1 entry via CXCR4. Preferably, but not necessarily, such peptides would not block the ability of CXCR4 to bind its natural ligand, SDF-1.
Ideally, selective inhibitors of HIV infection should comprise small molecule drugs. In contrast to other large protein-based therapeutics such as monoclonal antibodies, such small agents are advantageous since they are more likely to be non-immunogenic, orally administrable, and amenable for chemical synthesis and modification.
There is further need for improved chemokine peptides useful as therapeutic agents which provide enhanced activity and/or stability over existing chemokine peptides.
SUMMARY OF THE INVENTION
It is an object of the invention to provide antiviral synthetic peptides capable of inhibiting HIV-1 infection, by inhibiting HIV-1 mediated cytopathogenesis and cell fusion.
It is an object to provide a method of treating or inhibiting HIV-1 infection, by administration of the synthetic peptides.
It is an object of the invention to provide other synthetic chemokine peptides with enhanced properties.
The antiviral compounds of the present invention are in the form of peptides which possess anti-HIV activity. They inhibit HIV-1 entry into HIV-1 infection susceptible cells via the CXC chemokine receptor 4.
In all embodiments, the peptide may optionally comprise an amino-terminal and/or carboxy-terminal protecting group.
According to one embodiment, the invention is a peptide of the formula
X
1
-A-B-C-D-X
2
-E-F-G-X
3
-L-X
4
-J-K-M-N-P-Q-R-S-T-V-Ala-W-Y-X
5
  (I)
wherein:
X
1
is from zero to eight amino acids,
X
2
is three amino acids,
X
3
is from zero to eight amino acids,
L is a linker comprising a covalent bond or chemical moiety,
X
4
is from zero to eight amino acids,
X
5
is from zero to eight amino acids,
A is Ile, Leu, Phe or Val,
B is Ser or Thr
C is Phe, Tyr, or Trp,
D is Arg, His or Lys,
E is Arg, His or Lys,
F is Phe, Tyr, Trp or Leu
G is Phe, Tyr, Trp or Leu
J is Ile, Leu, Phe or Val,
K is Arg, Lys or His,
M is Phe, Tyr or Trp
N is Ile, Leu, Phe or Val,
P is Asn, Asp, Glu or Gin
Q is Asn, Asp, Glu or Gin
R is Tyr, Trp or Phe,
S is Ile, Leu, Phe or Val,
T is Asn, Asp, Glu or Gin
V is Arg, Lys or His,
W is Ile, Leu, Phe or Val,
Y is Asn, Asp, Glu or Gln, and said peptide optionally comprises an amino-terminal and/or carboxy-terminal protecting group.
In preferred embodiments, A is Leu, B is Ser, C is Tyr, D is Arg, E is Arg, F is Phe, G is Phe, J is Leu, K is Lys, M is Trp, N is Ile, P is Gln, Q is Glu, R is Tyr, S is Leu, T is Glu, V is Lys, W is Leu and/or Y is Asn.
In preferred embodiments, each of X
1
, X
3
, X
4

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