N-terminal modifications of RANTES and methods of use

Details N-terminal modifications of RANTES and methods of use N-terminal modifications of RANTES and methods of use

1998-08-28

2001-01-02

Celsa, Bennett (Department: 1627)

Drug, bio-affecting and body treating compositions

Lymphokine

C514S002600, C514S012200, C536S063000, C536S063000

Utility Patent

active

06168784

ABSTRACT:

TECHNICAL FIELD
The invention relates to N-terminally modified RANTES derivatives that effectively lock the inflammatory effects of RANTES, and are thus useful for the treatment of asthma, allergic rhinitis, atopic dermatitis, atheroma/atheroschleosis, and rheumatoid arthritis. Additionally, the compounds are useful for the treatment of human immune deficiency virus (“HIV”).
BACKGROUND
The protein known as RANTES is a member of a large family of cytokines known as chemokines, and is classified as a &bgr;-chemokine. It has a sixty-eight amino acid sequence (SEQ ID NO:1). A receptor for RANTES has recently been cloned (Gao, et al.,
J. Exp. Med
. 177:1421-7 (1993); Neote, et al.,
Cell
72:415-25 (1993)), which has been shown to bind chemokines in the order of potency of MIP-1&agr;>RANTES.
Chemokines have the ability to recruit and activate a wide variety of proinflammatory cell types, and RANTES has been shown to elicit an inflammatory response in vivo. RANTES, along with the natural ligands for the CCR5 chemokine receptor, MIP-1&agr;, MIP-1&bgr;, were found to inhibit human immune deficiency virus type-1 (“HIV-1”) infection (Cocchi, et al.,
Science
270:1811-1815 (1995)), leading to the identification of CCR5 as the major co-receptor for primary isolates of HIV-1, HIV-2 and SIV-1 (Deng, et al.,
Nature
381:661-666 (1996); Doranz, et al.,
Cell
85:1149-1158 (1996); Choe, et al.,
Cell
85:1135-1148 (1996); Chen, et al.,
J. Virol
. 71:2705-2714 (1997); and Alkhatib, et al.,
Science
272:1955-1958 (1996)). However, although RANTES consistently inhibits HIV-1 replication in peripheral blood mononuclear cells, it does not block infection of primary macrophage cultures, which suggests that RANTES would not influence HIV replication in non-lymphocyte cell types.
N-terminal modifications of RANTES result in antagonists that can block HIV-1 infection without signaling calcium flux (Mack, et al.,
J. Exp. Med
. 187:1215-1224 (1998) and Proudfoot, et al.,
J. Biol. Chem
. 271:2599-2603 (1996)). These modifications include N-terminal truncation [RANTES 9-68] (Arenzana-Seisdedos, et al.,
Nature
383:400 (1996)), and addition of methionine (“Met-RANTES”) or aminooxypentane (“AOP-RANTES”) at the N-terminus of RANTES (Mack, et al., supra and Simmons, et al.,
Science
276:276-279 (1997)). It has been reported that the Met-RANTES and AOP-RANTES derivatives are antagonists of RANTES. Further, N-terminally modified RANTES, with a higher affinity for CCR5 than native RANTES are more potent than native RANTES in blocking infection (Simmons, et al., supra).
Chemokine receptor antagonists that are potent, selective, and achieve full receptor occupancy would clearly be useful for the treatment of HIV-1 in infected individuals. Surprisingly, compounds have been discovered with this spectrum of activity. These derivatives inhibited infection of many different cell types, including macrophages and lymphocytes.
Additionally, antagonists of RANTES effectively block its inflammatory effects, and are thus useful for the treatment of asthma, allergic rhinitis, atopic dermatitis, viral diseases, atheroma/atheroschleosis, rheumatoid arthritis and organ transplant rejection.
Certain derivatives of RANTES are disclosed in Wells, et al., International Application WO 96/17935.
SUMMARY OF THE INVENTION
The polypeptides provided by the present invention are derivatives of RANTES modified at the N-terminus; they are antagonists of RANTES, and/or of MIP-1&agr;, and/or MIP-1&bgr;.
The polypeptides have the general formula:
R
1
-RANTES (2-68) (SEQ ID NO:2)
where R
1
is CH
3
—(CH
2
)
n
—X—; in which X is —C(O)—NH—CH
2
—C(O)—, —NHCH
2
—C(O)—, —ONH—CH
2
—C(O)—, —OCH
2
—CH
2
—C(O)—, —CH═CH—C(O)—, —C(O)—, or a covalent bond; and n is an integer from 4-8.
Also provided are pharmaceutical compositions and methods of treating disease states, including HIV infection, by administering therapeutically effective amounts of compounds comprising RANTES derivatives, or pharmaceutically acceptable salts thereof.
The invention also provides for polypeptides of the formula R
1
-RANTES (2-68) (SEQ ID NO:2) that have been modified by the grafting of polyethylene glycol (“PEG”) chains or PEG-based chains onto the RANTES portion of the polypeptide.


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