Chemistry: natural resins or derivatives; peptides or proteins; – Proteins – i.e. – more than 100 amino acid residues
Reexamination Certificate
1994-09-16
2003-06-24
Martinell, James (Department: 1631)
Chemistry: natural resins or derivatives; peptides or proteins;
Proteins, i.e., more than 100 amino acid residues
Reexamination Certificate
active
06583266
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to non-naturally occurring nucleic acid and peptides corresponding to nucleic acid and peptides of
Mycobacterium tuberculosis
and
Mycobacterium leprae
. The nucleic acid and peptides of the present invention have utility for diagnostics and therapeutics.
BACKGROUND OF THE INVENTION
Mycobacterium tuberculosis
is the causative agent of tuberculosis. Tuberculosis is a chronic bacterial infection characterized by the formation of granulomas in infected tissues and by cell mediated hypersensitivity. The usual site of the disease is the lungs but other organs may be involved. In countries where human immuno-deficiency virus (HIV) infection is endemic, tuberculosis is a frequent cause of morbidity in AIDS patients. Tuberculosis has shown a resurgence in recent years worldwide. Mycobacteria contain an array of protein and polysaccharide antigens giving rise to a cell mediated hypersensitivity. The hypersensitivity is often used to diagnose tuberculosis and to monitor the disease pathogenesis. See:
Harrison's Principles of Internal Medicine
, Twelfth Edition, McGraw-Hill, Inc., (1991), pp. 637-645.
Mycobacterium leprae
is the causative agent of Hanson's disease or leprosy. Leprosy is a chronic infection of superficial tissues, especially the skin and peripheral nerves.
Mycobacterium leprae
multiplies slowly, and has not been grown in tissue culture or artificial media.
Mycobacterium leprae
does not elicit strong immunological responses in infected individuals. However, a serodiagnostic test for the detection of antibody to
Mycobacterium leprae
antigen is used to aid in the diagnosis. See Harrison, supra, pp. 645-648.
Patient care, as well as the prevention and transmission of
Mycobacterium tuberculosis
and
leprae
, requires reliable diagnostic and prognostic tools to detect nucleic acid, antigens and antibodies relating to tuberculosis and leprosy.
A number of therapeutic agents are currently available for combatting
Mycobacterium tuberculosis
and
Mycobacterium leprae
infections in man. However, limitations to these therapies, particularly for
Mycobacterium tuberculosis
infection, demonstrate that new, more effective agents are needed. For example, agents such as isoniazid and rifampicin are currently in use for
Mycobacterium tuberculosis
infections, but strains which are resistant to one or the other or both of these agents are being reported with increasing frequency (eg., Chawla et al., 1992, Am. Rev. Respir. Dis. 146, 278-279). In addition,
Mycobacterium tuberculosis
bacilli treated by drug therapy frequently remain viable, but dormant as latent infections in macrophage phagolysosomes which may re-emerge as full-blown tuberculosis at a later date (eg., Dannenberg, in “The Mycobacteria: A Sourcebook”, Kubica and Wayne, eds., Dekker, N.Y., pp. 721-760).
BRIEF DESCRIPTION OF THE INVENTION
This invention relates to diagnostics and therapeutics for
Mycobacterium tuberculosis, M. leprae
and other mycobacterial species including, but not limited to:
M. avium, M. bovis, M. chitae, M. fortuitum, M. gorodonae, M. intracellulare, M. kansaii, M. paratuberculosis, M. smegmatis, M. terrae
, and
M. ulcerans
. One embodiment of the present invention features, as an article of manufacture or as a composition, a non-naturally occurring nucleic acid having twenty or more nucleotides in a sequence corresponding to a sequence of
Mycobacterium tuberculosis
or
Mycobacterium leprae
nucleic acid. The non-naturally occurring nucleic acid of the present invention is exemplified by Seq. ID No. 1 with respect to
Mycobacterium tuberculosis
and by Seq. ID Nos. 23-26 and 120-140 with respect to
Mycobacterium leprae
. Preferably, the sequence has at least twenty, and more preferably at least thirty nucleotides in a sequence corresponding to
Mycobacterium tuberculosis
or
Mycobacterium leprae
nucleic acid. The sequence may correspond to the entire coding sequence for the gene or a part of the coding sequence. However, sequences larger than 1000 nucleotides in length are difficult to synthesize.
One embodiment of the present invention features a non-naturally occurring nucleic acid wherein the nucleic acid encodes a peptide of
Mycobacterium tuberculosis
or
M. leprae
or other mycobacterial species. The peptide has utility for diagnostics and therapeutics.
A further embodiment of the present invention comprises a non-naturally occurring nucleic acid wherein the nucleic acid is capable of binding messenger RNA of
Mycobacterium tuberculosis
or
M. leprae
or other mycobacterial species. Such non-naturally occurring nucleic acid is capable of acting as anti-sense nucleic acid to control the translation of messenger RNA of
Mycobacterium tuberculosis, M. leprae
or other mycobacterial species. The non-naturally occurring nucleic acid inhibits the translation of
Mycobacterium tuberculosis, M. leprae
or other mycobacterial gene products, which by way of example, relate to the synthesis of antibiotics and the constituents of the cell wall, intermediary metabolism, transport processes, nucleic acid biosynthesis and modification, and antibiotic resistance. One of ordinary skill in the art would readily be able to discern which proteins were involved in the above metabolic processes. The above listed processes, as well as the proteins involved in such processes, are well described in any cellular biology textbook such as Molecular Cell Biology, Darnell, J., Lodish, H., and Baltimore, D. Scientific American Books, N.Y. Such non-naturally occurring nucleic acids have utility in therapeutics and diagnostics. A further embodiment of the present invention features a non-naturally occurring nucleic acid which nucleic acid is capable of binding specifically to
Mycobacterium tuberculosis
or
leprae
nucleic acid. Such non-naturally occurring nucleic acid has utility as probes and as capture reagents.
One embodiment of the present invention features an expression system comprising an open reading frame of DNA corresponding to
Mycobacterium tuberculosis
or
leprae
DNA. The nucleic acid further comprises a control sequence compatible with an intended host. The expression system is useful for making peptides corresponding to
Mycobacterium tuberculosis
or
leprae
nucleic acid.
A further embodiment of the present invention features a cell transformed with the expression system to make
Mycobacterium tuberculosis
or
leprae
proteins and peptides.
Several non-naturally occurring nucleic acids of the present invention feature nucleic acid relating to products involved in cell wall biosynthesis of
Mycobacterium tuberculosis
. Such nucleic acids have sequences of twenty or more nucleotides which correspond to sequences of Seq. ID No. 1. One such nucleic acid has a sequence of twenty or more nucleotides which correspond to a sequence within nucleotides 28,325 to 31,285 of Seq. ID No. 1. Nucleotides 28,325 to 31,285 encode a gene for polyketide or fatty acid synthesis. The gene codes for an enzyme with acyl transferase, enoyl reductase and dehydratase domains. The putative amino acid sequence of the gene product is set forth in Seq. ID No. 2.
An enzyme, ketoacyl ACP synthase of
Mycobacterium tuberculosis
, is encoded by nucleotides 26750 to 28237 of Seq. ID No. 1. The putative amino acid sequence of the enzyme is set forth in Seq. ID No. 3.
Nucleic acid encoding a gene for the enzyme beta-keto reductase of
Mycobacterium tuberculosis
corresponds to nucleotides 24636 to 26753 of Seq. ID No. 1. The putative amino acid sequence is set forth in Seq. ID No. 4.
Nucleic acid encoding COA ligases correspond to nucleotides 22136 to 23371 or 23251 to 23994 of Seq. ID No. 1. The putative amino acid sequence is set forth in Seq. ID No. 5 and Seq. ID No. 118.
Nucleic acids encoding two UDP-sugar transferases of
Mycobacterium tuberculosis
corresponds to nucleotides 9489 to 10846 of Seq. ID No. 1 and 12604 to 13995 of Seq. ID No. 1. The putative amino acid sequence are set forth in Seq. ID Nos. 6 and 7.
Nucleic acid encoding a methyltransf
Mao Jen-i
Smith Douglas R.
Genome Therapeutics Corporation
Martinell James
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