Lin Hong Hong

US Patent:

6545127, Apr 8, 2003

Filed:

Jun 27, 2000

Appl. No.:

09/604608

Inventors:

Xinli Lin - Edmond OK
Gerald Koelsch - Oklahoma City OK
Lin Hong - Oklahoma City OK

Assignee:

Oklahoma Medical Research Foundation - Oklahoma City OK

International Classification:

G01N 3348

US Classification:

530350, 702 19, 530300, 536 231

Abstract:

Methods for the production of purified, catalytically active, recombinant memapsin 2 have been developed. The substrate and subsite specificity of the catalytically active enzyme have been determined. The substrate and subsite specificity information was used to design substrate analogs of the natural memapsin 2 substrate that can inhibit the function of memapsin 2. The substrate analogs are based on peptide sequences, shown to be related to the natural peptide substrates for memapsin 2. The substrate analogs contain at least one analog of an amide bond which is not capable of being cleaved by memapsin 2. Processes for the synthesis of two substrate analogues including isosteres at the sites of the critical amino acid residues were developed and the substrate analogues, OMR99-1 and OM99-2, were synthesized. OM99-2 is based on an octapeptide Glu-Val-Asn-Leu-Ala-Ala-Glu-Phe (SEQ ID NO:28) with the Leu-Ala peptide bond substituted by a transition-state isostere hydroxyethylene group (FIG. ). The inhibition constant of OM99-2 is 1.

US Patent:

7829669, Nov 9, 2010

Filed:

Aug 3, 2007

Appl. No.:

11/888920

Inventors:

Gerald Koelsch - Oklahoma City OK, US
Lin Hong - Oklahoma City OK, US
Arun K. Ghosh - West Lafayette IN, US
Xinli Lin - Costa Mesa CA, US

Assignee:

Oklahoma Medical Research Foundation - Oklahoma City OK
The Board of Trustees of the University of Illinois - Urbana IL

International Classification:

C07K 1/00

US Classification:

530350

Abstract:

Methods for the production of purified, catalytically active, recombinant memapsin 2 have been developed. The substrate and subsite specificity of the catalytically active enzyme have been determined. The substrate and subsite specificity information was used to design substrate analogs of the natural memapsin 2 substrate that can inhibit the function of memapsin 2. The substrate analogs are based on peptide sequences, shown to be related to the natural peptide substrates for memapsin 2. The substrate analogs contain at least one analog of an amide bond which is not capable of being cleaved by memapsin 2. Processes for the synthesis of two substrate analogues including isosteres at the sites of the critical amino acid residues were developed and the substrate analogues, OMR99-1 and OM99-2, were synthesized. OM99-2 is based on an octapeptide Glu-Val-Asn-Leu-Ala-Ala-Glu-Phe (SEQ ID NO:28) with the Leu-Ala peptide bond substituted by a transition-state isostere hydroxyethylene group (FIG. ). The inhibition constant of OM99-2 is 1.

US Patent:

20020049303, Apr 25, 2002

Filed:

Feb 28, 2001

Appl. No.:

09/796264

Inventors:

Jordan Tang - Edmond OK, US
Xinli Lin - Edmond OK, US
Gerald Koelsch - Oklahoma City OK, US
Lin Hong - Oklahoma City OK, US

International Classification:

C12N015/09
C12N009/64
C12N015/74

US Classification:

530/350000, 435/069100, 435/252300, 435/320100, 435/006000, 435/069200, 514/002000, 530/387900

Abstract:

Methods for the production of purified, catalytically active, recombinant memapsin 2 have been developed. The substrate and subsite specificity of the catalytically active enzyme have been determined. The substrate and subsite specificity information was used to design substrate analogs of the natural memapsin 2 substrate that can inhibit the function of memapsin 2. The substrate analogs are based on peptide sequences, shown to be related to the natural peptide substrates for memapsin 2. The substrate analogs contain at least one analog of an amide bond which is not capable of being cleaved by memapsin 2. Processes for the synthesis of two substrate analogs including isosteres at the sites of the critical amino acid residues were developed and the substrate analogs, OMR99-1 and OM99-2, were synthesized. OM99-2 is based on an octapeptide Glu-Val-Asn-Leu-Ala-Ala-Glu-Phe (SEQ ID NO:28) with the Leu-Ala peptide bond substituted by a transition-state isostere hydroxyethylene group (FIG. ). The inhibition constant of OM99-2 is 1.6×10M against recombinant pro-memapsin 2. Crystallography of memapsin 2 bound to this inhibitor was used to determine the three dimensional structure of the protein, as well as the importance of the various residues in binding. This information can be used by those skilled in the art to design new inhibitors, using commercially available software programs and techniques familiar to those in organic chemistry and enzymology, to design new inhibitors to memapsin 2, useful in diagnostics and for the treatment and/or prevention of Alzheimer's disease.

US Patent:

20020115600, Aug 22, 2002

Filed:

Apr 30, 2001

Appl. No.:

09/845226

Inventors:

Gerald Koelsch - Oklahoma City OK, US
Jordan Tang - Edmond OK, US
Lin Hong - Oklahoma City OK, US
Arun Ghosh - River Forest IL, US

Assignee:

Oklahoma Medical Research Foundation

International Classification:

A61K038/17
A61K038/00

US Classification:

514/012000, 435/184000, 530/326000

Abstract:

Methods for the production of purified, catalytically active, recombinant memapsin 2 have been developed. The substrate and subsite specificity of the catalytically active enzyme have been determined. The substrate and subsite specificity information was used to design substrate analogs of the natural memapsin 2 substrate that can inhibit the function of memapsin 2. The substrate analogs are based on peptide sequences, shown to be related to the natural peptide substrates for memapsin 2. The substrate analogs contain at least one analog of an amide bond which is not capable of being cleaved by memapsin 2. Processes for the synthesis of two substrate analogues including isosteres at the sites of the critical amino acid residues were developed and the substrate analogues, OMR99-1 and OM99-2, were synthesized. OM99-2 is based on an octapeptide Glu-Val-Asn-Leu-Ala-Ala-Glu-Phe (SEQ ID NO:28) with the Leu-Ala peptide bond substituted by a transition-state isostere hydroxyethylene group (FIG. ). The inhibition constant of OM99-2 is 1.6×10M against recombinant pro-memapsin 2. Crystallography of memapsin 2 bound to this inhibitor was used to determine the tliree dimensional structure of the protein, as well as the importance of the various residues in binding. This information can be used by those skilled in the art to design new inhibitors, using commercially available software programs and techniques familiar to those in organic chemistry and enzymology, to design new inhibitors to memapsin 2, useful in diagnostics and for the treatment and/or prevention of Alzheimer's disease.

US Patent:

20040121947, Jun 24, 2004

Filed:

Oct 23, 2002

Appl. No.:

10/281092

Inventors:

Arun Ghosh - River Forest IL, US
Jordan Tang - Edmond OK, US
Geoffrey Bilcer - Oklahoma City OK, US
Wanpin Chang - Edmond OK, US
Lin Hong - Oklahoma City OK, US
Gerald Koelsch - Oklahoma City OK, US
Jeffrey Loy - Norman OK, US
Robert Turner - Oklahoma City OK, US

International Classification:

A61K038/16
C07K014/00

US Classification:

514/012000, 514/007000, 530/350000

Abstract:

Compounds inhibit memapsin 2 -secretase activity and selectively inhibit memapsin 2 -secretase activity relative to memapsin 1 -secretase activity. The compounds are employed in methods to inhibit memapsin 2 -secretase activity, in the treatment of Alzheimer's disease, in the inhibition of hydrolysis of a -secretase site of a amyloid precursor protein and to decrease -amyloid protein in in vitro samples and in mammals. Proteins of memapsin 2 associated with compounds of the invention are crystallized.

US Patent:

20040220079, Nov 4, 2004

Filed:

Feb 6, 2004

Appl. No.:

10/773754

Inventors:

Gerald Koelsch - Oklahoma City OK, US
Jordan Tang - Edmond OK, US
Lin Hong - Oklahoma City OK, US
Arun Ghosh - River Forest IL, US

International Classification:

A61K031/00
G06F019/00
G01N033/48
G01N033/50

US Classification:

514/001000, 702/019000

Abstract:

Methods for the production of purified, catalytically active, recombinant memapsin 2 have been developed. The substrate and subsite specificity of the catalytically active enzyme have been determined. The substrate and subsite specificity information was used to design substrate analogs of the natural memapsin 2 substrate that can inhibit the function of memapsin 2. The substrate analogs are based on peptide sequences, shown to be related to the natural peptide substrates for memapsin 2. The substrate analogs contain at least one analog of an amide bond which is not capable of being cleaved by memapsin 2. Processes for the synthesis of two substrate analogues including isosteres at the sites of the critical amino acid residues were developed and the substrate analogues, OMR99-1 and OM99-2, were synthesized. OM99-2 is based on an octapeptide Glu-Val-Asn-Leu-Ala-Ala-Glu-Phe (SEQ ID NO:28) with the Leu-Ala peptide bond substituted by a transition-state isostere hydroxyethylene group (FIG. ). The inhibition constant of OM99-2 is 1.6×10M against recombinant pro-memapsin 2. Crystallography of memapsin 2 bound to this inhibitor was used to determine the three dimensional structure of the protein, as well as the importance of the various residues in binding. This information can be used by those skilled in the art to design new inhibitors, using commercially available software programs and techniques familiar to those in organic chemistry and enzymology, to design new inhibitors to memapsin 2, useful in diagnostics and for the treatment and/or prevention of Alzheimer's disease.

US Patent:

20060234944, Oct 19, 2006

Filed:

Oct 23, 2002

Appl. No.:

10/493439

Inventors:

Arun Ghosh - River Forest IL, US
Jordan Tang - Edmond OK, US
Geoffrey Bilcer - Chicago IL, US
Wanpin Chang - Edmond OK, US
Lin Hong - Oklahoma City OK, US
Gerald Koelsch - Oklahoma City OK, US
Jeff Loy - Norman OK, US
Robert Turner III - Oklahoma City OK, US

Assignee:

Oklahoma Medical Reseach Foundation - Oklahoma City OK
The Board of Trustees of the University of Illinois - Urbana IL

International Classification:

A61K 38/08
C07K 7/06

US Classification:

514017000, 530330000, 530329000

Abstract:

Compounds inhibit memapsin 2 β-secretase activity and selectively inhibit memapsin 2 β-secretase activity relative to memapsin 1 β-secretase activity. The compounds are employed in methods to inhibit memapsin 2 β-secretase activity, in the treatment of Alzheimer's disease, in the inhibition of hydrolysis of a β-secretase site of a β-amyloid precursor protein and to decrease β-amyloid protein in in vitro samples and in mammals. Proteins of memapsin 2 associated with compounds of the invention are crystallized.

US Patent:

20100267609, Oct 21, 2010

Filed:

Jun 9, 2009

Appl. No.:

12/481339

Inventors:

Arun K. GHOSH - West Lafayette IN, US
Geoffrey Bilcer - Edmond OK, US
Wanpin Chang - Edmond OK, US
Lin Hong - Oklahoma City OK, US
Gerald E. Koelsch - Oklahoma City OK, US
Jeffrey A. Loy - Norman OK, US

International Classification:

A61K 38/07
C07K 5/10
A61K 38/16
A61P 25/28

US Classification:

514 11, 530330, 514 212

Abstract:

Compounds inhibit memapsin 2 β-secretase activity and selectively inhibit memapsin 2 β-secretase activity relative to memapsin 1 β-secretase activity. The compounds are employed in methods to inhibit memapsin 2 β-secretase activity, in the treatment of Alzheimer's disease, in the inhibition of hydrolysis of a β-secretase site of a β-amyloid precursor protein and to decrease β-amyloid protein in in vitro samples and in mammals. Proteins of memapsin 2 associated with compounds of the invention are crystallized.