There are a number of viral diseases recognized as retroviral in origin in both humans and other animals. The most publicized such disease among humans is that caused by the human immunodeficiency virus (HIV) as either AIDS or ARC. Other such diseases, however, include hepatitis B and hepatitis delta. Among cats, retroviral diseases include those caused by the feline immunodeficiency virus (FIV) and the feline leukemia virus (FeLV). A number of other animal species also contract retroviral-caused infections, such as the Visna virus infections of ungulates.
There have been a number of approaches to the treatment of such diseases, none of them entirely successful. Over a million Americans and several million people worldwide are infected with HIV, and treatment with the experimental drug AZT, produced by Burroughs Wellcome, appears to be of some help although it is clear that AZT is unable to cure AIDS and is extremely toxic. Nevertheless, AZT has been a considerable commercial success. There is no doubt that there is a continuing need for more effective antiviral agents which are effective against retroviral infections in general, and against HIV in particular.
A related approach to that herein is described in PCT Application W088/00047, published Jan. 14, 1988 and incorporated herein by reference. This application describes various materials which can be administered separately to a microenvironment and there assembled to create an active conjugate. The copending parent application herein, U.S. Ser. No. 261,436, also incorporated herein by reference, focuses on microenvironment of retroviral infections, specifically the loci of infection by human immunodeficiency virus (HIV), and the possibility to administer nontoxic precursors of a drug which would self-assemble at the site of the HIV infection as advantageous in treating the disease and symptomology caused by this virus.
The present application, rather than relying on self-assembly at the site of infection, is directed to administering compounds which are preassembled, and which are related to those used as components in the assembly in the parent application. Certain additional art discusses compounds which are also related to those described and claimed herein.
The compound most closely related to the invention conjugates described herein is suramin sodium, which is a complex conjugate of trisodium sulfonate naphthyl derivatives and aromatic nuclei linked through amide linkages. The structure of suramin is ##STR1##
The effects of suramin on the treatment of AIDS and its mechanism of action have been studied by a number of workers (Balzarini, J., et al, Int J Cancer (1986) 37:451-457; Levine, A. M., et al, Annals Int Med (1986) 105:32-37; Broder, S., et al, Lancet (1985) 1:627-630; Cheson, B. D., et al, JAMA (1987) 258:1347-1351). In general, this compound has been found helpful in treatment, although its toxicity precludes its use as a single agent in treatment. Side effects include ophthalmic damage, hypoadrenalism, nausea, thrombocytopenia and vomiting, and some deaths have been attributed to these side effects.
It has been suggested that the antiviral mechanism of suramin is due to binding of the polyanionic molecule to reverse transcriptase (DeClercq, E., Cancer Lett (1979) 8:9-22) and a large number of suramin analogs have been prepared. A total of 90 suramin analogs, of which 57 showed the ability to inhibit HIV-I reverse transcriptase activity, and 24 of which were superior to suramin in this inhibition, were prepared by Jentsch, K. D., et al, J Gen Virol (1987) 68:2183-2192. A representative group of suramin analogs is shown in FIG. 1. All of these are bis(naphthalene polysulfonic) acids, show ID.sub.50 values in the range of 5-42 ug/ml and, like suramin, eliminate the cytopathic effect of HIV-I against MT4 cells at 50 ug/ml.
As stated above, suramin sodium is highly toxic; too toxic to be used clinically to treat HIV infection. The analogs so far prepared have similar drawbacks.
The conjugates of the herein invention appear to home to monocytes. It appears that monocytes and macrophages are an appropriate target for an antiviral agent directed to HIV or other retroviral infection. In AIDS patients, evidence of HIV-I infection has been observed in monocytes from a variety of tissues, including brain, peripheral blood, lymph nodes, skin, and lung (Pauza, C. D., et al, J Virol (1988) 62: (in press); Pauza, C. D., Cell Immunol (1988) 112:414-424) and human peripheral blood monocytes and monocyte-derived cell lines support viral replication in vitro. In addition, two other immunosuppressive retroviruses, MLDV and the Visna virus of ungulates, cause immunosuppression primarily by infecting monocytes.
Others have shown that monocytes act as a reservoir for virus in infection (Ho, D., et al, New Eng J Med (1987) 317:278-286; Klatzmann, D., et al, Immunol Today (1986) 7:291-296). Since few T-cells are actually infected with HIV-I in AIDS patients, and since it is known that infected monocytes can shed HIV-I envelope protein in soluble form, it is inferred that infected monocytes may mediate the loss of helper T-cells in these patients (Siliciano, R. F., et al, Cell (1988) 54:561-575).
The compounds of the present invention offer the capability to interfere with the life cycle of retroviruses in general, probably through interference with the activity of reverse transcriptase, and are thus useful as prophylactic and therapeutic agents in the treatment of retroviral infections.