Lyss

Details Lyss Lyss

1999-03-16

2001-01-16

Achutamurthy, Ponnathapu (Department: 1652)

Chemistry: molecular biology and microbiology

Enzyme , proenzyme; compositions thereof; process for...

Reexamination Certificate

active

06174714

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 lysyl tRNA synthetase family, hereinafter referred to as “lysS”.
BACKGROUND OF THE INVENTION
Chlamydiaceae is a family of obligate intracellular parasites. All members share a common developmental cycle. Chlamydia infect a wide range of vertebrate host, particularly humans.
Chlamydia trachomatis
is one of the two recognized species of Chlamydia. Human infections caused by
C. trachomatis.
are widespread. This species is one of the most common cause of sexually transmitted disease in the world. It is also one of the main causes of infertility in humans.
The frequency of
Chlamydia trachomatis
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
Chlamydia trachomatis
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.
Transfer RNA (“tRNA”) synthetases have a primary role in protein synthesis according to the following scheme: first, Enzyme+ATP+AA Enzyme.AA-AMP+Ppi, followed by Enzyme.AA-AMP+t-RNA Enzyme+AMP+AA-t-RNA, in which AA is an amino acid, ATP and AMP are the triphosphated and monophosphated forms of adenosine, respectively, and Ppi is inorganic pyrophosphate. Inhibition of this process leads to a reduction in the levels of charged t-RNA and this triggers a cascade of responses known as the stringent response, the result of which is the induction of a state of dormancy in the organism. As such, selective inhibitors of bacterial t-RNA synthetase have potential as antibacterial agents. One example of such is mupirocin, which is a selective inhibitor of isoleucyl t-RNA synthetase.
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 Synechocystis sp lysyl tRNA synthetase protein. See Kaneko et al., DNA Res. 3:109-136 (1996); SwissProt Accession Number P73443 (reciting sequence of Synechocystis sp KRS).
SUMMARY OF THE INVENTION
It is an object of the invention to provide polypeptides that have been identified as novel lysS 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 Synechocystis sp lysyl tRNA synthetase protein.
It is a further object of the invention to provide polynucleotides that encode lysS polypeptides, particularly polynucleotides that encode the polypeptide herein designated lysS.
In a particularly preferred embodiment of the invention the polynucleotide comprises a region encoding lysS 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 lysS protein from
Chlamydia trachomatis
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
Chlamydia trachomatis
D/UW-3/Cx strain.
A further aspect of the invention there are provided isolated nucleic acid molecules encoding lysS, particularly
Chlamydia trachomatis
lysS, 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 lysS and polypeptides encoded thereby.
Another aspect of the invention there are provided novel polypeptides of
Chlamydia trachomatis
referred to herein as lysS 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 lysS polypeptide encoded by naturally occurring alleles of the lysS gene.
In a preferred embodiment of the invention there are provided methods for producing the aforementioned lysS 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 lysS expression, treating disease, for example, classic ocular trachoma, inclusion conjunctivitis, genital trachoma, infant pneumonitis, Lymphogranuloma Venerium, incipient trachoma, keratitis, papillary hypertrophy, corneal infiltration, vulvovaginitis, ear infection, mucopurulent rhinitis, salpingitis, cervicitis, cervical follicles, prostatitis, proctitis, urethritis, lymphogranule inguinale, climatic bubo, tropical bubo, and esthiomene., assaying genetic variation, and administering a lysS polypeptide or polynucleotide to an organism to raise an immunological response against a bacteria, especially a
Chlamydia trachomatis
bacteria.
In accordance with certain preferred embodiments of this and other aspects of the invention there are provided polynucleotides that hybridize to lysS polynucleotide sequences, particularly under stringent conditions.
In certain preferred embodiments of the invention there are provided antibodies against lysS polypeptides.
In other embodiments of the invention there are provided methods for identifying compounds which bind to or otherwise interact with and inhibit or activate an activity of a polypeptide or polynucleotide of the invention comprising: contacting a polypeptide or polynucleotide of the invention with a compound to be screened under conditions to permit binding to or other interaction between the compound and the polypeptide or polynucleotide to assess the binding to or other interaction with the compound, such binding or interaction being associated with a second component capable of providing a detectable signal in response to the binding or interaction of the polypeptide or polynucleotide with the compound; and determining whether the compound binds to or otherwise interacts with and activates or inhibits an activity of the polypeptide or polynucleotide by detecting the presence or absence of a signal generated from the binding or interaction of the compound with the polypeptide or polynucleotide.
In accordance with yet another aspect of the invention, there are provided lysS agonists and antagonists, preferably bacteriostatic or bacteriocidal agonists and antagonists.
In a further aspect of the invention there are provided compositions comprising a lysS polynucleotide or a lysS polypeptide for administration to a cell or to a multicellular organism.
Various changes and modifications within the spirit and scope of the disclosed invention will become readily apparent to those skil

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