Peptides and compounds that bind to a receptor

Abstract

Described are peptides and peptide mimetics that bind to and activate the thrombopoietin receptor. Such peptides and peptide mimetics are useful in methods for treating hematological disorders and particularly, thrombocytopenia resulting from chemotherapy, radiation therapy, or bone marrow transfusions as well as in diagnostic methods employing labeled peptides and peptide mimetics.

1 - 18 . (canceled)  
     
     
         19 . A compound that binds to a thrombopoietin receptor, wherein said compound comprises (H-IEGPTLRQ(2-NaI)LAARX 10 ) 2 K-NH2, wherein X 10  is selected from the group consisting of sarcosine and β-alanine.  
     
     
         20 . The compound of claim  1 , wherein said compound is covalently attached to a hydrophilic polymer.  
     
     
         21 . The compound of  claim 20 , wherein said hydrophilic polymer has an average molecular weight of between about 500 to about 40,000 daltons.  
     
     
         22 . The compound of  claim 20 , wherein said hydrophilic polymer has an average molecular weight of between about 5,000 to about 20,000 daltons.  
     
     
         23 . The compound of  claim 20 , wherein said polymer is selected from the group consisting of polyethylene glycol, polypropylene glycol, polylactic acid and poly glycolic acid.  
     
     
         24 . The compound of  claim 23 , wherein said compound is covalently attached to polyethylene glycol.  
     
     
         25 . The compound of  claim 19 , wherein each of the dimeric subunits of said compound is covalently attached to a hydrophilic polymer.  
     
     
         26 . A pharmaceutical composition comprising a compound of  claim 19  in combination with a pharmaceutically acceptable carrier.  
     
     
         27 . A method for treating a patient suffering from a disorder that is susceptible to treatment with a thrombopoietin agonist, comprising administering to the patient a therapeutically effective dose or amount of a compound of  claim 19 .  
     
     
         28 . A method of activating a thrombopoietin receptor in a cell, comprising contacting said cell with an effective amount of a compound which comprises (H-IEGPTLRQ(2-NaI)LAARX 10 ) 2 K-NH2, wherein X 10  is selected from the group consisting of sarcosine and β-alanine.  
     
     
         29 . A method according to  claim 28  wherein said cells comprise human megakaryocytes, platelets or CD34+ cells.  
     
     
         30 . A method according to  claim 28  wherein said cells comprise TPO-dependent cells.  
     
     
         31 . A method of treating thrombocytopenia in a subject, comprising: (a) obtaining a population of said subject's cells comprising megakaryocyte precursor cells; (b) treating said cells according to the method of  claim 28;  and (c) administering said treated cells to said subject, to increase the number of megakaryocytes present in said subject compared to that which would occur without such treatment.  
     
     
         32 . A method according to  claim 31  wherein said thrombocytopenia is due to chemotherapy.  
     
     
         33 . A method according to  claim 32  where said population of cells is obtained prior to chemotherapy.  
     
     
         34 . A method according to  claim 31  wherein said thrombocytopenia is due to radiation therapy.  
     
     
         35 . A method according to  claim 34  where said population of cells is obtained prior to said radiation therapy.  
     
     
         36 . A method of treating a patient suffering from thrombocytopenia, comprising administering to said patient a therapeutically effective dose of a compound which comprises (H-IEGPTLRQ(2-NaI)LAARX 10 ) 2 K-NH2, wherein X 10  is selected from the group consisting of sarcosine and β-alanine.  
     
     
         37 . A method according to  claim 36  wherein said thrombocytopenia is due to chemotherapy or radiation therapy.  
     
     
         38 . A method according to  claim 37  wherein a TPO antagonist is administered to said patient prior to said chemotherapy or radiation therapy.  
     
     
         39 . A method according to  claim 36  wherein said thrombocytopenia is due to bone marrow transfusion.  
     
     
         40 . A method of prophylactically treating a patient at risk of thrombocytopenia, comprising administering to said patient a prophylactically effective amount of a compound which comprises (H-IEGPTLRQ(2-NaI)LAARX 10 ) 2 K-NH2, wherein X 10  is selected from the group consisting of sarcosine and β-alanine.  
     
     
         41 . A method according to  claim 40  where said compound is administered prior to bone marrow transplantation, chemotherapy or radiation therapy.  
     
     
         42 . A compound that binds to thrombopoietin receptor, said compound having: 
 (i) a molecular weight of less than about 8000 daltons, and    (ii) a binding affinity to thrombopoietin receptor as expressed by an IC 50  of no more than about 100 μM, wherein said compound comprises the following sequence of amino acids:      X 9 X 8 G X 1 X 2 X 3 X 4  X 5 X 6 X 7      where X 9  is A,C,E, G, I, L, M, P, R, Q, S, T, or V; X 8  is A, C, D, E, K, L, Q, R, S, T, or V; X 1  is C, L, M, P, Q, V;    X 2  is F, K L, N, Q, R, S, T or V; X 3  is C, F, I, L, M, R, S, V or W;    X 4  is any of the 20 genetically coded L-amino acids;    X 5  is A, D, E, G, K, M, Q, R, S, T, V or Y;    X 7  is C, G, I, K, L, M, N, R or V, and    X 6  is β-(2-naphthyl)alanine.    
     
     
         43 . The compound of  claim 42 , wherein said sequence of amino acids is cyclized.  
     
     
         44 . The compound of  claim 42 , wherein said sequence of amino acids is dimerized.  
     
     
         45 . The compound of  claim 42 , wherein the compound comprises the following amino acid sequence: IEGPTLRQ (2-NaI) LAARA.