Antifungal and antibacterial agents

Details Antifungal and antibacterial agents Antifungal and antibacterial agents

2002-08-08

2004-09-14

Brumback, Brenda (Department: 1654)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Peptide containing doai

C514S011400, C514S014800, C424S550000, C435S007100, C435S069100, C435S183000, C530S350000

Reexamination Certificate

active

06790833

ABSTRACT:

FIELD OF THE INVENTION
This invention relates generally to antifungal and antibacterial agents, and more particularly to peptides generated from a human salivary mucin glycoprotein, MUC7.
BACKGROUND OF THE INVENTION
Many currently available antimicrobial agents have undesirable toxic effects, and a wide spread use of these drugs has lead to rapid development of drug resistant strains which are the leading cause for treatment failure. The need for efficient antimicrobial agents increases with the emergence of pathogens resistant to current therapies. Among the different approaches to find novel, safe and effective antimicrobial agents, the discovery and use of naturally occuring antimicrobial peptides is attracting increasing attention. This is because unlike many currently used antimicrobial compounds, they show little or no toxicity toward mammalian cells and low tendency to elicit resistance. The functional and structural properties, and therapeutic potential of the naturally occurring antimicrobial peptides (ribosomally synthesized), have recently been reviewed (1,2). With respect to structure and function, magainins (3), dermaseptins (4), cecropins, (5) and mammalian defensins (22) have been best characterized (1, 6). The majority of these peptides exhibit a random structure in water and a well-defined structure (&agr;-helical, &bgr;-sheet, extended structures and loops) in a simulated membrane-like environment (2). Their mode of antimicrobial action is not well understood. In most cases it is not mediated by receptors, but rather through peptide-microbial cell membrane lipid interaction, resulting in membrane permeation and cell lysis (7).
Human saliva has a fundamental importance in the host innate non-immune defense system against oral pathogens. Salivary mucins, together with other groups of salivary proteins (proline-rich proteins, cystatins, statherins and amylase) protect the oral cavity from microbial infections through more general protective mechanisms rather then the direct killing of microorganisms. The antimicrobial effect of mucins has largely been attributed to agglutination activity—trapping and clearing the microorganisms from the system. The selective binding of salivary mucins to microbial adhesins prevents the subsequent attachment of microorganisms to host surfaces (8,9). Conversely, mucins bound to tissues may serve as docking ports facilitating colonization of microorganisms like Streptococcus (10). Thus, salivary mucins play an intriguing, paradoxical role in the dynamics of the oral flora. The human saliva has been considered a potential source of naturally occurring antimicrobial agents. The human salivary non-immune defense system includes antimicrobial components such as the enzymes lactoferrin, lysozyme and peroxidase (11), as well as the histidine rich cationic peptides, histatins (12). Previous studies have shown that histatin-5 (24 amino acid peptide) (Hsn-5) possesses potent fungicidal activity in vitro against
Candida albicans
(
C. albicans
) (12). Further studies showed that Hsn-5 is targeted to mitochondria and that its cytotoxic activity depends on the metabolic activity of
C. albicans
. The killing of
C. albicans
by Hsn-5 is accomplished by an increase in membrane potential and permeability, and subsequent release of intracellular ATP (13,14). It was also shown that Hsn-5 and human neutophil defensin-1 kill
C. albicans
via a shared pathway (15).
Another component of human saliva is MUC7, a mucin glycoprotein consisting of 357 amino acid residues divided into 5 domains distinct in amino acid composition and function. Domain 1 constitutes the N-terminal 51 amino acid residues (MUC7 D1). While the parent MUC7 molecule does not exhibit fungicidal or bactericidal activity, it has been reported that synthetic 51 -mer exhibits excellent in vitro cidal activity against 8 clinical important fungal strains (including azole-resistant and amphotericin B-resistant fungi). However, there are no reports of MUC7D1 having antibacterial activity. The size of the MUC7D1 is not amenable to its use as an effective antifungal or anti-bactericidal agent. Moreover, larger peptides are more difficult to synthesize and harder to purify. Accordingly, there is a continuing need to develop novel antifungal and anti-bactericidal agents.


REFERENCES:
Reddy et al. Structural features of the low-molecular-mass human salivary mucin. Biochem. J. (1992) 287: 639-643.*
RN 28554-07-6. Mucin MG 2 (human clone MG2-6-1 gene MUC 7 percursor). Search Report (Jan. 2, 2003): HCAPLUS, Registry.*
Satyanarayana et al. Divergent solid-phase synthesis and candidacidal activity of MUC7 D1, a 51-residue histidine-rich N-terminal domain of human salivary mucin (MUC 7). J. Peptide Res. (2000) 56: 275-282. [Also cited in IDS, Paper No. 4].*
Database PIR-73 on GenCore 5.1.3 Accession No: A48018, 1993. Reference 1 (Reddy et al., 1992): SEQ ID No. 4-9.*
Gururaja, et al., Candidacidal Activity Prompted by N-Terminus Histatin-like Domain of Human Salivary Mucin (MUC-7), BBA 1431 (1999) pp. 107-119.
Satyanarayana, et al., Divergent Solid-phase Synthesis and Candidacidal Activity of MUC7 D1, a 51-Residue Histidine-rich N-terminal Domain of Human Salivary Mucin (MUC7), J. Peptide Res., 2000, 56, pp. 275-282.

Affiliated with

Also associated with

Rating

Antifungal and antibacterial agents does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with Antifungal and antibacterial agents, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Antifungal and antibacterial agents will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-3264798