US2003144479A1PendingUtilityA1
Biologically active compounds and methods of constructing and using the same
Priority: Jul 16, 1987Filed: Mar 25, 2002Published: Jul 31, 2003
Est. expiryJul 16, 2007(expired)· nominal 20-yr term from priority
Inventors:Mark I. GreeneWilliam V. WilliamsDavid B. WeinerJeffrey A. CohenThomas Kieber-EmmonsRobert M. Williams
C07K 16/1145A61K 39/00C07K 16/10C12N 2720/12022C07K 14/70539C12N 2740/16122C07K 14/005C07K 14/70514C07K 14/7051
57
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Claims
Abstract
A method of constructing biologically active compounds which mimic the biological activity of the biologically active protein or which block the activity of the biologically active protein is disclosed. A method of identifying specific and discrete portions of pathogen antigens which either serve as epitopes for neutralizing antibodies or which are involved in pathogen binding to host cell receptors is disclosed. A method of constructing biologically active compounds which compete with cellular receptors for binding to either biologically active proteins or pathogen antigens is disclosed.
Claims
exact text as granted — not AI-modified1 . A method of constructing a compound capable of eliciting in a mammal, a neutralizing immune response against a pathogen comprising the steps of:
a) generating a neutralizing antibody specific for an epitope of an antigen of said pathogen; b) generating an anti-idiotypic antibody specific for said neutralizing antibody; c) comparing amino acid sequences of said anti-idiotypic antibody and said epitope; and d) determining an amino acid sequence that corresponds to an amino acid sequence of said anti-idiotypic antibody and also corresponds to an amino acid sequence of said epitope.
2 . The method of claim 1 further comprising:
e) synthesizing a peptide comprising an amino acid sequence that corresponds to an amino acid sequence of said anti-idiotypic antibody and also corresponds to an amino acid sequence of said epitope.
3 . The method of claim 1 wherein said pathogen is a reovirus and said antigen is a haemagluttin sigma 1.
4 . The method of claim 1 wherein said pathogen is HIV and said antigen is a gp120.
5 . The method of claim 1 wherein said amino acid sequence of said anti-idiotypic antibody is an amino acid sequence of a complementarity determining region.
6 . The method of claim 2 further comprising the step of:
modifying said synthesized peptide to alter the three dimensional conformation thereof; and/or
modifying synthetic peptides by attaching connectors thereto and maintaining said synthetic peptides under conditions selected to allow formation of peptide dimers.
7 . A method of constructing a compound capable of preventing a biologically active protein or a pathogen from binding to a receptor which comprises the steps of:
a) generating an anti-receptor antibody capable of preventing said biologically active protein or said pathogen from binding to said receptor; b) comparing amino acid sequences of said anti-receptor antibody and said biologically active protein or an antigen of said pathogen; and c) determining an amino acid sequence that corresponds to an amino acid sequence of said anti-receptor antibody and also corresponds to an amino acid sequence of said biologically active protein or said antigen of said pathogen.
8 . The method of claim 7 further comprising:
d) synthesizing a peptide comprising an amino acid sequence that corresponds to an amino acid sequence of said anti-receptor antibody and also corresponds to an amino acid sequence of said biologically active protein or said antigen of said pathogen.
9 . The method of claim 7 wherein said pathogen is a reovirus and said receptor is a beta-adrenergic receptor-like structure which binds to haemagluttin and said antigen is a reovirus haemagluttin sigma 1.
10 . The method of claim 7 wherein said pathogen is HIV, said receptor is a CD4 molecule and said antigen is a gp120.
11 . The method of claim 7 wherein said amino acid sequence of said anti-receptor antibody is an amino acid sequence of a complementarity determining region.
12 . The method of claim 8 further comprising the step of:
modifying said synthesized peptide to alter the three dimensional conformation thereof; and/or
modifying synthetic peptides by attaching connectors thereto, and maintaining said synthetic peptides under conditions selected to allow formation of peptide dimers.
13 . A method of constructing a compound capable of preventing a pathogen or a biologically active protein from binding to a receptor which comprises the steps of:
a) generating an antibody specific for said biologically active protein or an antigen of said pathogen, said antibody being capable of preventing said biologically active protein or said pathogen from binding to said receptor; b) generating an anti-idiotypic antibody specific for said antibody; c) comparing amino acid sequences of said anti-idiotypic antibody and said biologically active protein or said antigen; and d) determining an amino acid sequence that corresponds to an amino acid sequence of said anti-idiotypic antibody and also corresponds to an amino acid sequence of said biologically active protein or said antigen.
14 . The method of claim 13 further comprising:
e) synthesizing a peptide comprising said amino acid sequence that corresponds to an amino acid sequence of said anti-idiotypic antibody and also corresponds to an amino acid sequence of said biologically active protein or said antigen.
15 . The method of claim 13 wherein said pathogen is a reovirus and said receptor is a beta-adrenergic receptor-like structure which binds to haemagluttin and said antigen is a haemagluttin sigma 1.
16 . The method of claim 13 wherein said pathogen is HIV, said receptor is a CD4 molecule and said antigen is a gp120.
17 . The method of claim 13 wherein said amino acid sequence of said anti-idiotypic antibody is an amino acid sequence of a complementarity determining region.
18 . The method of claim 14 further comprising the step of:
modifying said synthesized peptide and altering its three dimensional conformation; and/or,
modifying synthetic peptides by attaching connectors thereto, and maintaining said synthetic peptides under conditions selected to allow formation of peptide dimers.
19 . A method of constructing a biologically active compound comprising the steps of:
a) generating an anti-receptor antibody capable of effecting an activity or function of a cell; b) comparing amino acid sequences of said anti-receptor antibody and an antigen which binds to said receptor or a biologically active protein which binds to said receptor; and c) determining an amino acid sequence that corresponds to an amino acid sequence of said anti-receptor antibody and also corresponds to an amino acid sequence of said antigen or an amino acid sequence of said biologically active protein.
20 . The method of claim 19 further comprising:
e) synthesizing a peptide comprising an amino acid sequence that corresponds to an amino acid sequence of said anti-receptor antibody and also corresponds to an amino acid sequence of said antigen or an amino acid sequence of said biologically active protein.
21 . The method of claim 19 wherein said antigen is from a reovirus and said receptor is a beta-adrenergic receptor-like structure which binds to haemagluttin and said antigen is a haemagluttin sigma 1.
22 . The method of claim 19 wherein said amino acid sequence of said anti-receptor antibody is an amino acid sequence of a complementarity determining region.
23 . The method of claim 20 further comprising the step of:
modifying said synthesized peptide and altering its three dimensional conformation; and or,
modifying synthetic peptides by attaching connectors thereto and, maintaining said synthetic peptides under conditions selected to allow formation of peptide dimers.
24 . A synthetic biologically active peptide consisting essentially of an amino acid sequence corresponding to an amino acid sequence of an anti-idiotypic antibody or an anti-receptor antibody and also corresponding to an amino acid sequence of an antigen or biologically active protein.
25 . The peptide of claim 24 wherein said antigen is from a haemagluttin sigma 1 from a reovirus.
26 . The peptide of claim 24 wherein said antigen is gp120 from HIV.
27 . The peptide of claim 24 wherein said amino acid sequence of an anti-idiotypic antibody or anti-receptor antibody is an amino acid sequence of a complementarity determining region.
28 . The peptide of claim 24 comprising an amino acid sequence selected from the group consisting of:
Cys-Lys-Pro-Gly-Lys-Thr-Asn-Lys-Leu-Leu-Ile-Tyr-
Ser-Gly-Ser-Thr-Leu-Gln;
Lys-Pro-Gly-Lys-Thr-Asn-Lys-Leu-Leu-Ile-Phe-Ser-
Gly-Ser-Thr-Leu-Gln;
Lys-Pro-Gly-Lys-Thr-Asn-Lys-Leu-Leu-Ile-Tyr-Ala-
Gly-Ser-Thr-Leu-Gln;
Lys-Pro-Gly-Lys-Thr-Asn-Lys-LeU-Leu-Ile-Tyr-Ser-
Ala-Ser-Thr-Leu-Gln; and
Lys-Pro-Gly-Lys-Thr-Asn-Lys-Leu-Leu-Ile-Tyr-Ser-
Gly-Ser-Ala-Leu-Gln.
29 . The peptide of claim 24 wherein said peptide has an amino acid sequence consisting essentially of:
Cys-Lys-Pro-Gly-Lys-Thr-Asn-Lys-Leu-Leu-Ile-Tyr-
Ser-Gly-Ser-Thr-Leu-Gln;
Lys-Pro-Gly-Lys-Thr-Asn-Lys-Leu-Leu-Ile-Phe-Ser-
Gly-Ser-Thr-Leu-Gln;
Lys-Pro-Gly-Lys-Thr-Asn-Lys-Leu-Leu-Ile-Tyr-Ala-
Gly-Ser-Thr-Leu-Gln;
Lys-Pro-Gly-Lys-Thr-Asn-Lys-Leu-Leu-Ile-Tyr-Ser-
Ala-Ser-Thr-Leu-Gln; or
Lys-Pro-Gly-Lys-Thr-Asn-Lys-Leu-Leu-Ile-Tyr-Ser-
Gly-Ser-Ala-Leu-Gln.
30 . The peptide of claim 24 comprising an amino acid sequence selected from the group consisting of:
Lys-Pro-Gly-Lys-Thr-Asn-Lys-Leu-Leu-Ile-Tyr-Ser-
Gly-Ser-Thr-Leu-Gln;
Cys-Lys-Pro-Gly-Lys-Thr-Asn-Lys-Leu-Leu-Ile-Tyr-
Ser-Gly-Ser-Thr-Leu-Gln;
Lys-Pro-Gly-Lys-Thr-Asn-Lys-Cys-Leu-Ile-Tyr-Ser-
Gly-Ser-Thr-Cys-Gln;
Lys-Pro-Gly-Lys-Thr-Asn-Lys-Leu-Cys-Ile-Tyr-Ser-
Gly-Ser-Thr-Cys-Gln; and
Lys-Pro-Gly-Lys-Thr-Asn-Lys-Leu-Leu-Cys-Tyr-Ser-
Gly-Ser-Thr-Cys-Gln.
31 . The peptide of claim 24 having an amino acid sequence consisting essentially of:
Lys-Pro-Gly-Lys-Thr-Asn-Lys-Leu-Leu-Ile-Tyr-Ser-
Gly-Ser-Thr-Leu-Gln;
Cys-Lys-Pro-Gly-Lys-Thr-Asn-Lys-Leu-Leu-Ile-Tyr-
Ser-Gly-Ser-Thr-Leu-Gln;
Lys-Pro-Gly-Lys-Thr-Asn-Lys-Cys-Leu-Ile-Tyr-Ser-
Gly-Ser-Thr-Cys-Gln;
Lys-Pro-Gly-Lys-Thr-Asn-Lys-Leu-Cys-Ile-Tyr-Ser-
Gly-Ser-Thr-Cys-Gln; or
Lys-Pro-Gly-Lys-Thr-Asn-Lys-Leu-Leu-Cys-Tyr-Ser-
Gly-Ser-Thr-Cys-Gln.
32 . The peptide of claim 24 wherein said peptide is a dimer comprising a first peptide sequence and a second peptide sequence, wherein:
said first peptide sequence and said second peptide sequence may be the same or different;
each of said first peptide sequence and said second peptide sequence are identical or similar to similar portions of an antigen and an anti-idiotypic antibody for said antigen; and,
said dimer is joined at one end.
33 . The peptide of claim 24 wherein said peptide is a dimer comprising a first peptide sequence and a second peptide sequence, wherein:
said first peptide sequence and said second peptide sequence may be the same or different;
each of said first peptide sequence and said second peptide sequence are identical or similar to similar portions of an antigen and an anti-idiotypic antibody for said antigen; and,
said dimer is joined at one end by a sulfhydryl bond.
34 . The peptide dimer of claim 24 wherein said peptide is a dimer comprising a first peptide sequence and a second peptide sequence, wherein:
said first peptide sequence and said second peptide sequence may be the same or different;
each of said first peptide sequence and said second peptide sequence are identical or similar to similar portions of an antigen and an anti-idiotypic antibody for said antigen;
said dimer is joined at one end; and
said first peptide sequence comprises an amino acid sequence selected from the group consisting of:
Cys-Lys-Pro-Gly-Lys-Thr-Asn-Lys-Leu-Leu-Ile-Tyr- Ser-Gly-Ser-Thr-Leu-Gln, Cys-Lys-Pro-Gly-Lys-Thr-Asn-Lys-Leu-Leu-Ile-Phe- Ser-Gly-Ser-Thr-Leu-Gln, Cys-Lys-Pro-Gly-Lys-Thr-Asn-Lys-Leu-Leu-Ile-Tyr- Ala-Gly-Ser-Thr-Leu-Gln, Cys-Lys-Pro-Gly-Lys-Thr-Asn-Lys-Leu-Leu-Ile-Tyr- Ser-Ala-Ser-Thr-Leu-Gln, and Cys-Lys-Pro-Gly-Lys-Thr-Asn-Lys-Leu-Leu-Ile-Tyr- Ser-Gly-Ser-Ala-Leu-Gln;
and said second peptide sequences comprises an amino acid sequence selected from the group consisting of:
Cys-Lys-Pro-Gly-Lys-Thr-Asn-Lys-Leu-Leu-Ile-Tyr- Ser-Gly-Ser-Thr-Leu-Gln, Cys-Lys-Pro-Gly-Lys-Thr-Asn-Lys-Leu-Leu-Ile-Phe- Ser-Gly-Ser-Thr-Leu-Gln, Cys-Lys-Pro-Gly-Lys-Thr-Asn-Lys-Leu-Leu-Ile-Tyr- Ala-Gly-Ser-Thr-Leu-Gln, Cys-Lys-Pro-Gly-Lys-Thr-Asn-Lys-Leu-Leu-Ile-Tyr- Ser-Ala-Ser-Thr-Leu-Gln, and Cys-Lys-Pro-Gly-Lys-Thr-Asn-Lys-Leu-Leu-Ile-Tyr- Ser-Gly-Ser-Ala-Leu-Gln.
35 . A method of immunizing a host mammal against infection by a pathogen comprising the steps of:
a) generating a neutralizing antibody specific for an epitope of an antigen of said pathogen; b) generating an anti-idiotypic antibody specific for said neutralizing antibody; c) comparing amino acid sequences of said anti-idiotypic antibody and said epitope; d) determining an amino acid sequence that corresponds to an amino acid sequence of said anti-idiotypic antibody and also corresponds to an amino acid sequence of said epitope; e) synthesizing a peptide comprising an amino acid sequence that corresponds to an amino acid sequence of said anti-idiotypic antibody and also corresponds to an amino acid sequence of said epitope; and, f) inoculating said mammal with said synthetic peptide in an amount effective to reduce the likelihood that said host will be susceptible to infection by said pathogen.
36 . The method of claim 35 wherein said pathogen is a reovirus.
37 . The method of claim 35 wherein said synthetic peptide comprises the amino acid sequence selected from the group consisting of:
Cys-Lys-Pro-Gly-Lys-Thr-Asn-Lys-Leu-Leu-Ile-Tyr-
Ser-Gly-Ser-Thr-Leu-Gln,
Lys-Pro-Gly-Lys-Thr-Asn-Lys-Leu-Leu-Ile-Phe-Ser-
Gly-Ser-Thr-Leu-Gln,
Lys-Pro-Gly-Lys-Thr-Asn-Lys-Leu-Leu-Ile-Tyr-Ala-
Gly-Ser-Thr-Leu-Gln,
Lys-Pro-Gly-Lys-Thr-Asn-Lys-Leu-Leu-Ile-Tyr-Ser-
Ala-Ser-Thr-Leu-Gln, or
Lys-Pro-Gly-Lys-Thr-Asn-Lys-Leu-Leu-Ile-Tyr-Ser-
Gly-Ser-Ala-Leu-Gln.
38 . The method of claim 36 wherein said peptide is a dimer comprising a first peptide sequence and a second peptide sequence,
said first peptide sequence comprising an amino acid sequence selected from the group consisting of:
Cys-Lys-Pro-Gly-Lys-Thr-Asn-Lys-Leu-Leu-Ile-Tyr- Ser-Gly-Ser-Thr-Leu-Gln; Cys-Lys-Pro-Gly-Lys-Thr-Asn-Lys-Leu-Leu-Ile-Phe- Ser-Gly-Ser-Thr-Leu-Gln; Cys-Lys-Pro-Gly-Lys-Thr-Asn-Lys-Leu-Leu-Ile-Tyr- Ala-Gly-Ser-Thr-Leu-Gln; Cys-Lys-Pro-Gly-Lys-Thr-Asn-Lys-Leu-Leu-Ile-Tyr- Ser-Ala-Ser-Thr-Leu-Gln; and Cys-Lys-Pro-Gly-Lys-Thr-Asn-Lys-Leu-Leu-Ile-Tyr- Ser-Gly-Ser-Ala-Leu-Gln;
and said second peptide sequences comprising an amino acid sequence selected from the group consisting of:
Cys-Lys-Pro-Gly-Lys-Thr-Asn-Lys-Leu-Leu-Ile-Tyr- Ser-Gly-Ser-Thr-Leu-Gln; Cys-Lys-Pro-Gly-Lys-Thr-Asn-Lys-Leu-Leu-Ile-Phe- Ser-Gly-Ser-Thr-Leu-Gln; Cys-Lys-Pro-Gly-Lys-Thr-Asn-Lys-Leu-Leu-Ile-Tyr- Ala-Gly-Ser-Thr-Leu-Gln; Cys-Lys-Pro-Gly-Lys-Thr-Asn-Lys-Leu-Leu-Ile-Tyr- Ser-Ala-Ser-Thr-Leu-Gln; and Cys-Lys-Pro-Gly-Lys-Thr-Asn-Lys-Leu-Leu-Ile-Tyr- Ser-Gly-Ser-Ala-Leu-Gln.
39 . A method of treating a host mammal to prevent or reduce the severity of an infection by a pathogen comprising the steps of:
a) generating an anti-receptor antibody against a receptor which said pathogen binds to in infection, said anti-receptor antibodies capable of preventing said pathogen from binding to said receptor; b) comparing amino acid sequences of said anti-receptor antibody and said an antigen of said pathogen; c) determining an amino acid sequence that corresponds to an amino acid sequence of said anti-receptor antibody and also corresponds to an amino acid sequence of said antigen; d) synthesizing a peptide comprising said amino acid sequence that corresponds to an amino acid sequence of said anti-receptor antibody and also corresponds to an amino acid sequence of said antigen; e) inoculating said mammal with said synthetic peptide in an amount effective to prevent or reduce the likelihood of said pathogen infecting cells of said host.
40 . The method of claim 39 wherein said pathogen is a reovirus.
41 . The method of claim 39 wherein said synthetic peptide comprises the amino acid sequence selected from the group consisting of:
Cys-Lys-Pro-Gly-Lys-Thr-Asn-Lys-Leu-Leu-Ile-Tyr-
Ser-Gly-Ser-Thr-Leu-Gln;
Lys-Pro-Gly-Lys-Thr-Asn-Lys-Leu-Leu-Ile-Phe-Ser-
Gly-Ser-Thr-Leu-Gln;
Lys-Pro-Gly-Lys-Thr-Asn-Lys-Leu-Leu-Ile-Tyr-Ala-
Gly-Ser-Thr-Leu-Gln;
Lys-Pro-Gly-Lys-Thr-Asn-Lys-Leu-Leu-Ile-Tyr-Ser-
Ala-Ser-Thr-Leu-Gln; and,
Lys-Pro-Gly-Lys-Thr-Asn-Lys-Leu-Leu-Ile-Tyr-Ser-
Gly-Ser-Ala-Leu-Gln.
42 . The method of claim 39 wherein said peptide is a dimer which comprises a first peptide sequence and a second peptide sequence,
said first peptide sequence comprising an amino acid sequence selected from the group consisting of:
Cys-Lys-Pro-Gly-Lys-Thr-Asn-Lys-Leu-Leu-Ile-Tyr- Ser-Gly-Ser-Thr-Leu-Gln; Cys-Lys-Pro-Gly-Lys-Thr-Asn-Lys-Leu-Leu-Ile-Phe- Ser-Gly-Ser-Thr-Leu-Gln; Cys-Lys-Pro-Gly-Lys-Thr-Asn-Lys-Leu-Leu-Ile-Tyr- Ala-Gly-Ser-Thr-Leu-Gln; Cys-Lys-Pro-Gly-Lys-Thr-Asn-Lys-Leu-Leu-Ile-Tyr- Ser-Ala-Ser-Thr-Leu-Gln; and, Cys-Lys-Pro-Gly-Lys-Thr-Asn-Lys-Leu-Leu-Ile-Tyr- Ser-Gly-Ser-Ala-Leu-Gln;
and said second peptide sequences comprises an amino acid sequence selected from the group consisting of:
Cys-Lys-Pro-Gly-Lys-Thr-Asn-Lys-Leu-Leu-Ile-Tyr- Ser-Gly-Ser-Thr-Leu-Gln; Cys-Lys-Pro-Gly-Lys-Thr-Asn-Lys-Leu-Leu-Ile-Phe- Ser-Gly-Ser-Thr-Leu-Gln; Cys-Lys-Pro-Gly-Lys-Thr-Asn-Lys-Leu-Leu-Ile-Tyr- Ala-Gly-Ser-Thr-Leu-Gln; Cys-Lys-Pro-Gly-Lys-Thr-Asn-Lys-Leu-Leu-Ile-Tyr- Ser-Ala-Ser-Thr-Leu-Gln; and, Cys-Lys-Pro-Gly-Lys-Thr-Asn-Lys-Leu-Leu-Ile-Tyr- Ser-Gly-Ser-Ala-Leu-Gln.
43 . A method of effecting or altering activity or function of a mammalian cell comprising:
a) generating an anti-receptor antibody capable of effecting an activity or function of said cell; b) comparing amino acid sequences of said anti-receptor antibody and a biologically active protein which can bind to said receptor and effect an activity or function of said cell; and c) determining an amino acid sequence that corresponds to an amino acid sequence of said anti-receptor antibody and also corresponds to an amino acid sequence of said biologically active protein; d) synthesizing a peptide comprising an amino acid sequence that corresponds to an amino acid sequence of said anti-receptor antibody and also corresponds to an amino acid sequence of said biologically active protein; e) contacting said cell with said synthesized peptide, said synthetic peptide being present in an amount effective to effect or alter activity or function of said cell.
44 . The method of claim 43 wherein said biologically active protein is an antigen of a pathogen.Join the waitlist — get patent alerts
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