Therapy of atherosclerosis, primary biliary cirrhosis and nrlp3 inflammasome-associated disease by htcp inhibitors

Abstract

An inhibitor of Na+-taurocholate cotransporting polypeptide (NTCP) for use in a method of treatment of primary biliary cirrhosis, atherosclerosis, or an NRLP3 inflammasome-associated disease in a subject.

1 . An inhibitor of Na+-taurocholate cotransporting polypeptide (NTCP) for use in a method of treatment of primary biliary cirrhosis, atherosclerosis, or an NRLP3 inflammasome-associated disease in a subject. 
     
     
         2 . The NTCP inhibitor for use of  claim 1 , wherein the NTCP inhibitor is a pre-S1 peptide inhibitor, wherein the pre-S1 peptide inhibitor comprises a peptide comprising amino acid sequence NPLGFX 0 P (SEQ ID NO: 15), and wherein X 0  is any amino acid, preferably F or L, more preferably F. 
     
     
         3 . The NTCP inhibitor for use of  claim 2 , wherein the pre-S1 peptide inhibitor further comprises an N-terminal sequence of at least 4 amino acids at the N-terminus of NPLGFX 0 P (SEQ ID NO: 15), wherein preferably the N-terminal sequence comprises amino acid sequence NX 1 SX 2 X 3  (SEQ ID NO: 16), wherein X 1 , X 2  and X 3  is any amino acid, wherein preferably
 X 1  is L, I or Q, preferably L;   X 2  is T, V, A or is absent, preferably T or V, more preferably T; and/or   X 3  of is P, S, T or F, preferably P or S, more preferably S.   
     
     
         4 . The NTCP inhibitor for use of  claim 2 , wherein the pre-S1 peptide inhibitor further comprises a C-terminal sequence of at least 1 amino acid at the C-terminus of NPLGFX 0 P (SEQ ID NO: 15), wherein preferably the C-terminal sequence comprises amino acid sequence X 4 HQLDP (SEQ ID NO: 18), wherein X 4  is any amino acid, wherein preferably X 4  is D, E or S, preferably D or E, more preferably D. 
     
     
         5 . The NTCP inhibitor for use of  claim 2 , wherein of the pre-S1 peptide inhibitor comprises or consists of 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118 or 119 amino acids. 
     
     
         6 . The NTCP inhibitor for use of  claim 2 , wherein of the pre-S1 peptide inhibitor comprises a pre-S1 peptide of an HBV virus, or a functional fragment thereof, wherein the function is preferably binding to NTCP, inhibition of NTCP, or reduction of NTCP activity, wherein preferably the pre-S1 peptide inhibitor comprises or consists of:
 at least amino acids 9 to 15, 8 to 15, 7 to 15, 6 to 15, 5 to 15, 4 to 15, 3 to 15, 2 to 15 of a pre-S1 peptide of an HBV virus;   at least amino acids 9 to 16, 9 to 17, 9 to 18, 9 to 19, 9 to 20, 9 to 21, 9 to 22, 9 to 23, 9 to 24, 9 to 25, 9 to 26, 9 to 27, 9 to 28, 9 to 29, 9 to 30, 9 to 31, 9 to 32, 9 to 33, 9 to 34, 9 to 35, 9 to 36, 9 to 37, 9 to 38, 9 to 39, 9 to 40, 9 to 41, 9 to 42, 9 to 43, 9 to 44, 9 to 45, 9 to 46, 9 to 47, 9 to 48 of a pre-S1 peptide of an HBV virus;   at least amino acids 8 to 16, 7 to 17, 6 to 18, 5 to 19, 4 to 20, 3 to 21, or 2 to 22 of a pre-S1 peptide of an HBV virus;   at least amino acids 2 to 15, 2 to 16, 2 to 17, 2 to 18, 2 to 19, 2 to 19, 2 to 20, 2 to 21, 2 to 22, 2 to 23, 2 to 24, 2 to 252 to 26, 2 to 27, 2 to 28, 2 to 29, 2 to 30, 2 to 31, 2 to 32, 2 to 33, 2 to 34, 2 to 35, 2 to 36, 2 to 37, 2 to 38, 2 to 39, 2 to 40, 2 to 41, 2 to 42, 2 to 43, 2 to 44, 2 to 45, 2 to 46, 2 to 47, or 2 to 48 of a pre-S1 peptide of an HBV virus;   at least amino acids 9 to 15 and 16 to 20 of a pre-S1 peptide of an HBV virus;   at least amino acids 2 to 8 and 9 to 15 of a pre-S1 peptide of an HBV virus;   at least amino acids 2 to 8, 9 to 15 and 16 to 20 of a pre-S1 peptide of an HBV virus;   at least amino acids 9 to 15 and 34 to 48 of a pre-S1 peptide of an HBV virus;   at least amino acids 9 to 15, 16 to 20 and 34 to 48 of a pre-S1 peptide of an HBV virus;   at least amino acids 2 to 8, 9 to 15 and 34 to 48 of a pre-S1 peptide of an HBV virus;   at least amino acids 2 to 8, 9 to 15, 16 to 20 and 34 to 48 of a pre-S1 peptide of an HBV virus;   at least amino acids 2 to 48 of a pre-S1 peptide of an HBV virus or a portion thereof of at least 15 amino acids;   amino acids 2 to 48 of a pre-S1 peptide of an HBV virus; or   a sequence having at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95% identity with any of the above sequences.   
     
     
         7 . The NTCP inhibitor for use of  claim 6 , wherein the HBV virus is HBV strain alpha1, HBV strain LSH, woodchuck HBV, Woolly Monkey HBV (WMHBV), orangutan HBV, chimpanzee HBV, gorilla HBV, human HBV, HBV subtype AD, ADR, ADW, ADYW, AR or AYW, or HBV genotype A, B, C, D, E, F, G or H. 
     
     
         8 . The NTCP inhibitor for use of  claim 2 , wherein the pre-S1 peptide inhibitor comprises or consists of amino acid sequence 
       
         
           
                 
               
                   (SEQ ID NO: 1) 
                 
                   (-11)-M GGWSS TPRKG MGTNL SVPNP LGFFP DHQLD PAFRA 
                 
                     
                 
                   NSNNP DWDFN PNKDH WPEAN KVG-48 
                 
                     
                 
                   (SEQ ID NO: 2) 
                 
                   (-11)-M GGWSS KPRKG MGTNL SVPNP LGFFP DHQLD PAFGA 
                 
                     
                 
                   NSNNP DWDFN PVKDD WPAAN QVG-48 
                 
                     
                 
                   (SEQ ID NO: 3) 
                 
                   (-11)-M GGWSS KPRKG MGTNL SVPNP LGFFP DHQLD PAFKA 
                 
                     
                 
                   NSENP DWDLN PHKDN WPDAN KVG-48 
                 
                     
                 
                   (SEQ ID NO: 4) 
                 
                   (-11)-M GGWSS KPRQG MGTNL SVPNP LGFFP DHQLD PAFGA 
                 
                     
                 
                   NSNNP DWDFN PNKDH WPEAN QVG-48 
                 
                     
                 
                   (SEQ ID NO: 5) 
                 
                   1-MGQNL STSNP LGFFP DHQLD PAFRA NTANP DWDFN PNKDT 
                 
                     
                 
                   WPDAN KVG-48 
                 
                     
                 
                   SEQ ID NO: 6) 
                 
                   (-10)-MGLSW TVPLE WGKNI STTNP LGFFP DHQLD PAFRA 
                 
                     
                 
                   NTRNP DWDHN PNKDH WTEAN KVG-48 
                 
                     
                 
                   (SEQ ID NO: 7) 
                 
                   (-11)-M GAPLS TTRRG MGQNL SVPNP LGFFP DHQLD PLFRA 
                 
                     
                 
                   NSSSP DWDFN TNKDS WPMAN KVG-48 
                 
                     
                 
                   (SEQ ID NO: 8) 
                 
                   (-10)-MGLSW TVPLE WGKNL SASNP LGFLP DHQLD PAFRA 
                 
                     
                 
                   NTNNP DWDFN PKKDP WPEAN KVG-48 
                 
                     
                 
                   (SEQ ID NO: 9) 
                 
                   (-11)-M GAPLS TARRG MGQNL SVPNP LGFFP DHQLD PLFRA 
                 
                     
                 
                   NSSSP DWDFN TNKDN WPMAN KVG-48 
                 
                     
                 
                   (SEQ ID NO: 10) 
                 
                   1-MGLNQ STFNP LGFFP SHQLD PLFKA NAGSA DWDKN PNKDP 
                 
                     
                 
                   WPQAH DTA 
                 
                     
                 
                   (SEQ ID NO: 11) 
                 
                   (-11)-M GGWSS KPRQG MGTNL SVPNP LGFFP DHQLD PAFGA 
                 
                     
                 
                   NSNNP DWDFN PNKDH WPEAN KVG-48, 
                 
             
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
               
            
           
         
       
       or
 a fragment thereof of at least 15 amino acids, or 
 a sequence having at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95% identity with any of the above sequences, 
 wherein preferably the pre-S1 peptide inhibitor comprises or consists of amino acid sequence 
 
       
         
           
                 
                 
               
                     
                   (SEQ ID NO: 12) 
                 
                     
                   GTNL SVPNP LGFFP DHQLD PAFRA NSNNP DWDFN PNKDH 
                 
                     
                     
                 
                     
                   WPEAN KVG; 
                 
                     
                     
                 
                     
                   (SEQ ID NO: 13) 
                 
                     
                   GTNL SVPNP LGFFP DHQLD PAFGA NSNNP DWDFN PNKDH 
                 
                     
                     
                 
                     
                   WPEAN KVG; 
                 
                     
                     
                 
                     
                   (SEQ ID NO: 14) 
                 
                     
                   GTNL SVPNP LGFFP DHQLD PAFGA NSNNP DWDFN PNKDH 
                 
                     
                     
                 
                     
                   WPEAN QVG; 
                 
             
                
                
                
                
                
                
                
                
                
                
                
                
                
                
               
            
           
         
       
       or
 a sequence having at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95% identity with any of the above sequences. 
 
     
     
         9 . The NTCP inhibitor for use of  claim 2 , wherein the pre-S1 peptide inhibitor is modified by at least one hydrophobic moiety at the N-terminus or in 1, 2, 3, or 4 amino acids proximity to the N-terminus, wherein the hydrophobic moiety modification is preferably acylation, wherein the acylation is preferably an acylation with myristoyl (C14), palmitoyl (C16), or stearoyl (C18). 
     
     
         10 . The NTCP inhibitor for use of  claim 2 , wherein the pre-S1 peptide inhibitor is Myristoyl-GTNLSVPNPLGFFPDHQLDPAFGANSNNPDWDFNPNKDHWPEANKVG-amide. 
     
     
         11 . The NTCP inhibitor for use of  claim 2 , wherein the method comprises administering the pre-S1 inhibitor and a further NTCP inhibitor. 
     
     
         12 . The NTCP inhibitor for use of  claim 1 , wherein the subject is a human. 
     
     
         13 . The NTCP inhibitor for use of  claim 1 , wherein the method results in the reduction, or elimination of symptoms of primary biliary cirrhosis, wherein preferably the method results in normalization of biochemical parameters and decrease in inflammation and fibrosis progression. 
     
     
         14 . The NTCP inhibitor for use of  claim 1 , wherein the atherosclerosis is at a stage of unstable atherosclerotic plaques and wherein the method results in the reduction, resolution or elimination of atherosclerotic plaques. 
     
     
         15 . The NTCP inhibitor for use of  claim 1 , wherein the NRLP3 inflammasome-associated disease is type-2 diabetes, atherosclerosis, gout, Alzheimer's disease and NASH.