Apt

Details Apt Apt

1999-10-14

2002-02-19

Devi, S. (Department: 1645)

Chemistry: natural resins or derivatives; peptides or proteins;

Proteins, i.e., more than 100 amino acid residues

C530S300000, C530S825000, C424S094500, C424S244100, C424S234100, C424S190100, C424S185100

Reexamination Certificate

active

06348578

ABSTRACT:

FIELD OF THE INVENTION
This invention relates to newly identified polynucleotides and polypeptides, and their production and uses, as well as their variants, agonists and antagonists, and their uses. In particular, in these and in other regards, the invention relates to novel polynucleotides and polypeptides of the apt (adenine phosphoribosyltransferase) family, hereinafter referred to as “apt”.
BACKGROUND OF THE INVENTION
The Streptococci make up a medically important genera of microbes known to cause several types of disease in humans, including, for example, otitis media, conjunctivitis, pneumonia, bacteremia, meningitis, sinusitis, pleural empyema and endocarditis, and most particularly meningitis, such as for example infection of cerebrospinal fluid. Since its isolation more than 100 years ago,
Streptococcus pneumoniae
has been one of the more intensively studied microbes. For example, much of our early understanding that DNA is, in fact, the genetic material was predicated on the work of Griffith and of Avery, Macleod and McCarty using this microbe. Despite the vast amount of research with
S. pneumoniae,
many questions concerning the virulence of this microbe remain. It is particularly preferred to employ Streptococcal genes and gene products as targets for the development of antibiotics.
The frequency of
Streptococcus pneumoniae
infections has risen dramatically in the past 20 years. This has been attributed to the emergence of multiply antibiotic resistant strains and an increasing population of people with weakened immune systems. It is no longer uncommon to isolate
Streptococcus pneumoniae
strains which are resistant to some or all of the standard antibiotics. This has created a demand for both new anti-microbial agents and diagnostic tests for this organism.
While certain Streptococcal factors associated with pathogenicity have been identified, e.g., capsule polysaccharides, peptidoglycans, pneumolysins, PspA Complement factor H binding component, autolysin, neuraminidase, peptide permeases, hydrogen peroxide, IgAl protease, the list is certainly not complete. Moreover, very little is known concerning the temporal expression of such genes during infection and disease progression in a mammalian host. Discovering the sets of genes the bacterium is likely to be expressing at the different stages of infection, particularly when an infection is established, provides critical information for the screening and characterization of novel antibacterials which can interrupt pathogenesis. In addition to providing a fuller understanding of known proteins, such an approach will identify previously unrecognised targets.
Purine nucleotides may be derived from exogenous purines by the so-called salvage pathways, or they may be synthesised de novo from simpler precursors. The salvage pathways fulfill several functions. One is to scavenge exogenous, preformed bases and nucleosides for nucleotide synthesis, and another is to reutilise bases and nucleosides produced endogenously as a result of nucleotide turnover. A third is catabolic, whereby the pentose moieties of exogenous nucleosides and the amino groups of adenine compounds are made available as sources of carbon and nitrogen, respectively. Adenine is converted to AMP by adenine phosphoribosyltransferase (encoded by apt) and to adenosine by purine nucleoside phosphorylase (deoD gene). These enzymes play a key role in bacterial metabolism and therefore inhibitors of these proteins could prevent the bacterium from establishing and maintaining infection of the host and thereby have utility in anti-bacterial therapy.
Clearly, there is a need for factors, such as the novel compounds of the invention, that have a present benefit of being useful to screen compounds for antibiotic activity. Such factors are also useful to determine their role in pathogenesis of infection, dysfunction and disease. There is also a need for identification and characterization of such factors and their antagonists and agonists which can play a role in preventing, ameliorating or correcting infections, dysfunctions or diseases.
The polypeptides of the invention have amino acid sequence homology to a known
E. coli
apt protein. See Hershey, H. V. and Taylor, M. W., “Nucleotide sequence and deduced amino acid sequence of
Escherichia coli
adenine phosphoribosyl-transferase and comparison with other analogous enzymes”,
Gene,
43, 287-293 (1986) and SWISS-PROT, Accession Number P07672 relating to the sequence of adenine phosphoribosyltranferase (apt) of
E. coli;
also see Hochstadt, J., “Adenine phosphoribosyltransferase from
Escherichia coli”, Methods Enzymol.,
51, 558-567 (1978).
SUMMARY OF THE INVENTION
It is an object of the invention to provide polypeptides that have been identified as novel apt polypeptides by homology between the amino acid sequence set out in Table 1 [SEQ ID NO: 2] and a known amino acid sequence or sequences of other proteins such as
E. coli
apt protein.
It is a further object of the invention to provide polynucleotides that encode apt polypeptides, particularly polynucleotides that encode the polypeptide herein designated apt.
In a particularly preferred embodiment of the invention the polynucleotide comprises a region encoding apt polypeptides comprising the sequence set out in Table 1 [SEQ ID NO:1] which includes a full length gene, or a variant thereof.
In another particularly preferred embodiment of the invention there is a novel apt protein from Streptococcus pneumoniae comprising the amino acid sequence of Table 1 [SEQ ID NO:2], or a variant thereof.
In accordance with another aspect of the invention there is provided an isolated nucleic acid molecule encoding a mature polypeptide expressible by the
Streptococcus pneumoniae
0100993 strain contained in the deposited strain.
A further aspect of the invention there are provided isolated nucleic acid molecules encoding apt, particularly
Streptococcus pneumoniae
apt, including mRNAs, cDNAs, genomic DNAs. Further embodiments of the invention include biologically, diagnostically, prophylactically, clinically or therapeutically useful variants thereof, and compositions comprising the same.
In accordance with another aspect of the invention, there is provided the use of a polynucleotide of the invention for therapeutic or prophylactic purposes, in particular genetic immunization. Among the particularly preferred embodiments of the invention are naturally occurring allelic variants of apt and polypeptides encoded thereby.
Another aspect of the invention there are provided novel polypeptides of Streptococcus pneumoniae referred to herein as apt as well as biologically, diagnostically, prophylactically, clinically or therapeutically useful variants thereof, and compositions comprising the same.
Among the particularly preferred embodiments of the invention are variants of apt polypeptide encoded by naturally occurring alleles of the apt gene.
In a preferred embodiment of the invention there are provided methods for producing the aforementioned apt polypeptides.
In accordance with yet another aspect of the invention, there are provided inhibitors to such polypeptides, useful as antibacterial agents, including, for example, antibodies.
In accordance with certain preferred embodiments of the invention, there are provided products, compositions and methods for assessing apt expression, treating disease, for example, otitis media, conjunctivitis, pneumonia, bacteremia, meningitis, sinusitis, pleural empyema and endocarditis, and most particularly meningitis, such as for example infection of cerebrospinal fluid, assaying genetic variation, and administering a apt polypeptide or polynucleotide to an organism to raise an immunological response against a bacteria, especially a
Streptococcus pneumoniae
bacteria.
In accordance with certain preferred embodiments of this and other aspects of the invention there are provided polynucleotides that hybridize to apt polynucleotide sequences, particularly under stringent conditions.
In certain preferred embodim

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