Anti-fungal peptides

Abstract

The present invention relates generally to anti-fungal peptides derived from or based on Domain III (amino acids 142-169) of bactericidal / permeability-increasing protein (BPI) and therapeutic uses of such peptides.

Description

[0001] This is a continuation of U.S. patent application Ser. No. 08 / 504,841 filed Jul. 20, 1995, which is herein incorporated by reference.BACKGROUND OF INVENTION[0002] The present invention relates generally to anti-fungal peptides derived from or based on Domain III (amino acids 142-169) of bactericidal / permeability-increasing protein (BPI) and therapeutic uses of such peptides.[0003] BPI is a protein isolated from the granules of mammalian polymorphonuclear leukocytes (PMNs or neutrophils), which are blood cells essential in the defense against invading microorganisms. Human BPI protein has been isolated from PMNs by acid extraction combined with either ion exchange chromatography [Elsbach, J. Biol. Chem., 254:11000 (1979)] or E. coli affinity chromatography [Weiss, et al, Blood, 69:652 (1987)]. BPI obtained in such a manner is referred to herein as natural BPI and has been shown to have potent bactericidal activity against a broad spectrum of gram-negative bacteria. The molecul...

AI Technical Summary

Problems solved by technology

In susceptible gram-negative bacteria, BPI binding is thought to disrupt LPS structure, leading to activation of bacterial enzymes that degrade phospholipids and peptidoglycans, altering the permeability of the cell's outer membrane, and initiating events that ultimately lead to cell death.

Amphotericin B is usually effective for systemic mycoses, but its administration is limited by toxic effects that include fever and kidney damage, and other accompanying side effects such as anemia, low blood pressure, headache, nausea, vomiting and phlebitis.

Significant inhibition of mammalian P450 results in significant drug interactions.

Miconazole is a parenteral imidazole with efficacy in coccidioidomycosis and several other mycoses, but has side effects including hyperlipidemia and hyponatremia.

The disease is noncontagious and ordinarily self-limited, but chronic pulmonary infection and disseminated infection may occur.

It also is usually self-limited but may lead to chronic pulmonary infection or disseminated infection.

Most pulmonary infections are probably self-limited.

It may be acute and self-limited or may produce progressive pulmonary disease or extrapulmonary dissemination.

Disseminated disease is generally fatal in the absence of therapy.

Sulfonamides may be used but have a low success rate.

Cryptococcosis is a particular problem in immunocompromised patients; cryptococcal meningitis occurs in 7 to 10% of AIDS patients.

Aspergillosis is increasing in prevalence and is particularly a problem among patients with chronic respiratory disease or immunocompromised patients.

Aspergillosis is also a rare but devastating complication of bum wounds; amputation is often required for cure.

Invasive aspergillosis is commonly fatal, so aggressive diagnosis and treatment is required.

Invasive systemic disease has become a problem due to the use of high doses of antibiotics that destroy normal bacterial flora, immunosuppressive agents, and agents toxic to bone marrow, e.g., during cancer therapy.

Neutropenia is a major risk factor for Candida dissemination.

Laryngeal involvement results in hoarseness.

These lesions are a potential cause of blindness.

Infection may result in progressive renal insufficiency.

Involvement of the lungs is also common, but pulmonary lesions are usually too small to be seen on chest X-ray.

Fungal lesions appear on the valves, and can embolize and occlude large blood vessels.

Systemic candidiasis may be difficult to diagnose because the presence of heavy colonization at the usual sites of infection indicates, but does not prove, that dissemination has occurred.

Even with therapy, however, complete cure of endocarditis is not always possible.

Both drugs have substantial adverse reactions when used in combination with cyclosporine A, which itself can be nephrotoxic.

In immunocompromised patients, however, these infections are problematic and resist effective treatment.

In particular, effective anti-fungal therapy for systemic mycoses is limited.

When made the subject of adjunctive therapy, the administration of Domain III derived peptides may reduce the amount of anti-fungal agent needed for effective therapy, thus limiting potential toxic response and / or high cost of treatment.

The peptide, through its heparin-binding ability, may interfere with the binding of fungi to the extracellular matrix.

In addition, the peptide may bind to fungal cell wall mannoproteins that are structurally similar to the LPS of gram-negative organisms or that are responsible for adherence to target host tissues, thus interfering with fungal interaction with host tissues.

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