Highest Known Catalytic Rate for Superoxide Dismutation Achieved

MetaPhore Researchers Use Computer-Aided Design to Create More Active Compound



Apr 25, 2001, 01:00 ET from MetaPhore Pharmaceuticals

    ST. LOUIS, April 25 /PRNewswire/ -- Researchers at MetaPhore
 Pharmaceuticals have used computer-aided design techniques to achieve a
 hundred-fold increase in the catalytic activity of one of the company's
 synthetic manganese-based compounds previously shown to exert protective
 anti-inflammatory effects in animal models.
     The compounds, part of a family being developed by MetaPhore, mimic the
 action of the body's prime free radical fighting natural enzyme, superoxide
 dismutase (SOD).  The original SOD mimetic compound developed by MetaPhore
 achieved catalytic rates approaching natural SOD.
     "The improved compound possesses the highest catalytic rate for superoxide
 dismutation of any known synthetic mimetic," said lead researcher, Dennis
 Riley, adding that the improved compound also exceeds the catalytic rate of
 natural copper, zinc and manganese SOD enzymes because it "actually increases
 in catalytic rate as the pH decreases."
     In a study published this month by the journal Inorganic Chemistry, the
 researchers also reported that the improved SOD enzyme mimetic, consistent
 with its enhanced catalytic rate, exhibited protective effects in animal
 models of reperfusion injury and septic shock at dosage levels one hundred
 times less than those required using the original SOD enzyme mimetic.
     The lower dosage plus retention of the original's high degree of stability
 makes the improved SOD mimetic an even more attractive candidate for use as a
 drug in humans.
     Riley and his team used computer-aided design processes, developed based
 on their unique understanding of how the original SOD mimetic functions as a
 catalyst, to circumvent the time consuming and expensive process of
 synthesizing and then testing countless molecular variations.
     "Once we understood the subtle and unobvious interplay between position,
 number and spatial arrangement of atoms and groups in dictating a molecule's
 catalytic activity, we were able to design highly complicated molecules and
 test their potential as catalysts," explained Riley.
     "Thus, we are now able to model any given molecular variation and
 calculate the expected catalytic rate," said Riley, "thereby giving us the
 capability to tailor a wide range of highly effective, very stable SOD
 mimetics for different disease states where free radical damage plays a role."
     The SOD enzyme plays a central role in the body's oxidative chemistry,
 regulating normal levels of free radical superoxide molecules.  In certain
 disease states, however, the body's immune system prompts an overproduction of
 superoxide free radicals and the natural SOD enzymes become overwhelmed,
 leading to tissue and cell damage.
 
     Background
     Production of superoxide, a free radical, results from cellular oxidative
 metabolism.  However, when too much superoxide is produced in the body,
 various biomolecules, cell structures and even genes are damaged.
 Free-radical damage has been linked with a wide range of diseases and
 conditions, including autoimmune and neurodegenerative disorders, multiple
 types of cancer, complications of diabetes mellitus, strokes, reperfusion
 injury, as well as pain and inflammation.
     One of the body's primary defense mechanisms against free-radical damage
 is the superoxide dismutase (SOD) family of enzymes.  These enzymes typically
 regulate normal levels of superoxide by converting it into hydrogen peroxide
 and oxygen, also reducing production of related damaging oxidants, such as
 peroxynitrite.
     MetaPhore is developing a proprietary family of drugs that mimic the
 catalytic activity of SOD to address the diseases and conditions resulting
 from excessive superoxide production.  In pre-clinical models, the lead
 candidate from this family has suggested the potential to combat such diseases
 and conditions more effectively and with fewer side effects than existing
 treatments.
     "SOD enzyme mimetics have major medical potential, based on the growing
 body of anti-oxidant and disease research.  For more than twenty years, we
 have understood the free-radical fighting power of the body's natural SOD
 enzymes, but until recently, we have been unable to reproduce that beneficial
 effect in a stable and selective drug form," said Dennis Riley, MetaPhore's
 Senior Vice President of Research & Development.
     MetaPhore's SOD enzyme mimetics are well suited for use as drugs because
 they have a low molecular weight, are highly stable and do not appear to
 elicit an immune response in the body.
     Animal studies published in journals such as Science and the Proceedings
 of the National Academy of Sciences during the past few years have confirmed
 the disease fighting potential of MetaPhore's SOD enzyme mimetics.  These
 studies have also demonstrated that MetaPhore's original SOD enzyme mimetic
 substantially reduces tissue damage due to inflammation and reperfusion
 injury -- the latter involving the return of blood flow following removal of
 blockade, such as after an ischemic heart attack or stroke.
     Statements in this press release that are not strictly historical are
 "forward looking" statements as defined in the Private Securities Litigation
 Reform Act of 1995.  The actual results may differ from those projected in the
 forward looking statement due to risks and uncertainties that exist in the
 company's operations, development efforts and business environment.
 
                     MAKE YOUR OPINION COUNT -  Click Here
                http://tbutton.prnewswire.com/prn/11690X47258075
 
 

SOURCE MetaPhore Pharmaceuticals
    ST. LOUIS, April 25 /PRNewswire/ -- Researchers at MetaPhore
 Pharmaceuticals have used computer-aided design techniques to achieve a
 hundred-fold increase in the catalytic activity of one of the company's
 synthetic manganese-based compounds previously shown to exert protective
 anti-inflammatory effects in animal models.
     The compounds, part of a family being developed by MetaPhore, mimic the
 action of the body's prime free radical fighting natural enzyme, superoxide
 dismutase (SOD).  The original SOD mimetic compound developed by MetaPhore
 achieved catalytic rates approaching natural SOD.
     "The improved compound possesses the highest catalytic rate for superoxide
 dismutation of any known synthetic mimetic," said lead researcher, Dennis
 Riley, adding that the improved compound also exceeds the catalytic rate of
 natural copper, zinc and manganese SOD enzymes because it "actually increases
 in catalytic rate as the pH decreases."
     In a study published this month by the journal Inorganic Chemistry, the
 researchers also reported that the improved SOD enzyme mimetic, consistent
 with its enhanced catalytic rate, exhibited protective effects in animal
 models of reperfusion injury and septic shock at dosage levels one hundred
 times less than those required using the original SOD enzyme mimetic.
     The lower dosage plus retention of the original's high degree of stability
 makes the improved SOD mimetic an even more attractive candidate for use as a
 drug in humans.
     Riley and his team used computer-aided design processes, developed based
 on their unique understanding of how the original SOD mimetic functions as a
 catalyst, to circumvent the time consuming and expensive process of
 synthesizing and then testing countless molecular variations.
     "Once we understood the subtle and unobvious interplay between position,
 number and spatial arrangement of atoms and groups in dictating a molecule's
 catalytic activity, we were able to design highly complicated molecules and
 test their potential as catalysts," explained Riley.
     "Thus, we are now able to model any given molecular variation and
 calculate the expected catalytic rate," said Riley, "thereby giving us the
 capability to tailor a wide range of highly effective, very stable SOD
 mimetics for different disease states where free radical damage plays a role."
     The SOD enzyme plays a central role in the body's oxidative chemistry,
 regulating normal levels of free radical superoxide molecules.  In certain
 disease states, however, the body's immune system prompts an overproduction of
 superoxide free radicals and the natural SOD enzymes become overwhelmed,
 leading to tissue and cell damage.
 
     Background
     Production of superoxide, a free radical, results from cellular oxidative
 metabolism.  However, when too much superoxide is produced in the body,
 various biomolecules, cell structures and even genes are damaged.
 Free-radical damage has been linked with a wide range of diseases and
 conditions, including autoimmune and neurodegenerative disorders, multiple
 types of cancer, complications of diabetes mellitus, strokes, reperfusion
 injury, as well as pain and inflammation.
     One of the body's primary defense mechanisms against free-radical damage
 is the superoxide dismutase (SOD) family of enzymes.  These enzymes typically
 regulate normal levels of superoxide by converting it into hydrogen peroxide
 and oxygen, also reducing production of related damaging oxidants, such as
 peroxynitrite.
     MetaPhore is developing a proprietary family of drugs that mimic the
 catalytic activity of SOD to address the diseases and conditions resulting
 from excessive superoxide production.  In pre-clinical models, the lead
 candidate from this family has suggested the potential to combat such diseases
 and conditions more effectively and with fewer side effects than existing
 treatments.
     "SOD enzyme mimetics have major medical potential, based on the growing
 body of anti-oxidant and disease research.  For more than twenty years, we
 have understood the free-radical fighting power of the body's natural SOD
 enzymes, but until recently, we have been unable to reproduce that beneficial
 effect in a stable and selective drug form," said Dennis Riley, MetaPhore's
 Senior Vice President of Research & Development.
     MetaPhore's SOD enzyme mimetics are well suited for use as drugs because
 they have a low molecular weight, are highly stable and do not appear to
 elicit an immune response in the body.
     Animal studies published in journals such as Science and the Proceedings
 of the National Academy of Sciences during the past few years have confirmed
 the disease fighting potential of MetaPhore's SOD enzyme mimetics.  These
 studies have also demonstrated that MetaPhore's original SOD enzyme mimetic
 substantially reduces tissue damage due to inflammation and reperfusion
 injury -- the latter involving the return of blood flow following removal of
 blockade, such as after an ischemic heart attack or stroke.
     Statements in this press release that are not strictly historical are
 "forward looking" statements as defined in the Private Securities Litigation
 Reform Act of 1995.  The actual results may differ from those projected in the
 forward looking statement due to risks and uncertainties that exist in the
 company's operations, development efforts and business environment.
 
                     MAKE YOUR OPINION COUNT -  Click Here
                http://tbutton.prnewswire.com/prn/11690X47258075
 
 SOURCE  MetaPhore Pharmaceuticals