Biologically active peptides from functional domains of bactericidal/permeability-increasing protein and uses thereof

Abstract

The present invention provides peptides having an amino acid sequence that is the amino acid sequence of a human bactericidal/permeability-increasing protein (BPI) functional domain or a subsequence thereof, and variants of the sequence or subsequence thereof, having at least one of the BPI biological activities, such as heparin binding, heparin neutralization, LPS binding, LPS neutralization or bactericidal activity. The invention provides peptides and pharmaceutical compositions of such peptides for a variety of therapeutic uses.

Description

Claims

1. A compound which is a peptide selected from the group consisting of:

______________________________________ASQQGTAALQKELKRIKIPDYSDSFKIKH (SEQ ID NO: 1);GTAALQKELKRIKIPDYSDSFKIKHLGKGH (SEQ ID NO: 2);LQKELKRIKIPDYSKSFKIKHL (SEQ ID NO: 3);QQGTAALQKELKRIK (SEQ ID NO: 4);andGTAALQKELKRIKIP (SEQ ID NO: 5).______________________________________

2. A compound which is a peptide selected from the group consisting of:

__________________________________________________________________________SSQISMVPNVGLKFSISNANIKISGKWKAQKRFLK (SEQ ID NO: 6);IKISGKWKAQKRFLK (SEQ ID NO: 7);KWKAQKRFLK (SEQ ID NO: 8);CIKISGKWKAQKRFLK (SEQ ID NO: 9);CIKISGKWKAQKRFLKC (SEQ ID NO: 10);NVGLKFSISNANIKISGKWKAQKRFLK (SEQ ID NO: 11);AKISGKWKAQKRFLK (SEQ ID NO: 16);IAISGKWKAQKRFLK (SEQ ID NO: 17);IKASGKWKAQKRFLK (SEQ ID NO: 18);IKIAGKWKAQKRFLK (SEQ ID NO: 19);IKISAKWKAQKRFLK (SEQ ID NO: 20);IKISGAWKAQKRFLK (SEQ ID NO: 21);IKISGKAKAQKRFLK (SEQ ID NO: 22);IKISGKWAAQKRFLK (SEQ ID NO: 23);IKISGKWKAAKRFLK (SEQ ID NO: 24);IKISGKWKAQARFLK (SEQ ID NO: 25);IKISGKWKAQKAFLK (SEQ ID NO: 26);IKISGKWKAQKRALK (SEQ ID NO: 27);IKISGKWKAQKRFAK (SEQ ID NO: 28);IKISGKWKAQKRFLA (SEQ ID NO: 29);IKISGAWAAQKRFLK (SEQ ID NO: 30);IKISGKWKAAARFLK (SEQ ID NO: 31);IAISGKWKAQKRFLA (SEQ ID NO: 32);IKISGKWKAKQRFLK (SEQ ID NO: 47);IKISGKFKAQKRFLK (SEQ ID NO: 48);IKISGKW.sub.D KAQKRFLK (SEQ ID NO: 49);IKISGKA.sub..beta.-(1-naphthyl) KAQKRFLK (SEQ ID NO: 50);KRFLKKWKAQKRFLK (SEQ ID NO: 51);KWKAQKRFLKKWKAQKRFLK (SEQ ID NO: 54);KRFLKKWKAQKRFLKKWKAQKRFLK (SEQ ID NO: 55);KWKAAARFLKKWKAQKRFLK (SEQ ID NO: 57);KWKAQKRFLKKWKAAARFLK (SEQ ID NO: 58);KWKAAARFLKKWKAAARFLK (SEQ ID NO: 59);KWKAAARFLKKWKAAARFLKKWKAAARFLK (SEQ ID NO: 60);IKISGKWKAQFRFLK (SEQ ID NO: 62);IKISGKA.sub..beta.-(1-naphthyl) KAQKRFLK (SEQ ID NO: 63);IIKISGKWKAQKRA.sub..beta.-(3-pyridyl) LK (SEQ ID NO: 64);QKRFLKKWKAQKRFLKKWKAQKRFLK (SEQ ID NO: 65);A.sub.D A.sub.D IKISGKWKAQKRFLK (SEQ ID NO: 66);IKISGKWKAQF.sub.D RFLK (SEQ ID NO: 71);IKISGKWKAQWRFLK (SEQ ID NO: 72);IKISGKWKAKKRFLK (SEQ ID NO: 73);IKISGKWKAQA.sub..beta.-(1-naphthyl) RFLK (SEQ ID NO: 74);IKISGKWKAFKRFLK (SEQ ID NO: 75);IKISGKA.sub..beta.-(1-naphthyl) KAQFRFLK (SEQ ID NO: 78);IKISGKWKAFFRFLK (SEQ ID NO: 82);IKISGKA.sub..beta.-(1-naphthyl) KAFKRFLK (SEQ ID NO: 84);IKISGKA.sub..beta.-(1-naphthyl) KAFFRFLK (SEQ ID NO: 85);KWKAQWRFLKKWKAQWRFLKKWKAQWRFLK (SEQ ID NO: 93);CIKISGKWKAQKRPLC (SEQ ID NO: 99);IKKRAISFLGKKWQK (SEQ ID NO: 100);IKISGKWKAWKRFLKK (SEQ ID NO: 102);IKISGKWKAWKRA.sub..beta.-(1-naphthyl) LKK (SEQ ID NO: 104);IKISGKA.sub..beta.-(1-naphthyl) KAQA.sub..beta.-(1-naphthyl) RFLK (SEQ ID NO: 111);KWQLRSKGKIKIFKA (SEQ ID NO: 113);IKISGKA.sub..beta.-(1-naphthyl) KAA.sub..beta.-(1-naphthyl) KRFLK (SEQ ID NO: 115);IKISGKWKAQKRKLK (SEQ ID NO: 116);IKISGKWKAA.sub..beta.-(1-naphthyl) A.sub..beta.-(1-naphthyl) RFLK (SEQ ID NO: 117);IKISGKA.sub..beta.-(1-naphthyl) KAA.sub..beta.-(1-naphthyl) A.sub..beta.-(1-naphthyl) RFLK (SEQ ID NO: 118);IKISGKWKAQERFLK (SEQ ID NO: 132);IKISGKWKAQKRWLK (SEQ ID NO: 137);IKISGKWKAEKKFLK (SEQ ID NO: 143);KWAFAKKQKKRLKRQWLKKF (SEQ ID NO: 148);KWKAQKRFLKKWKAQKAFLKKWKAQKRFLK (SEQ ID NO: 149);KWKAA.sub..beta.-(1-naphthyl) A.sub..beta.-(1-naphthyl) RFLKKWKAQKRFLK (SEQ ID NO: 150);KWKAQKRFLKKWKAA.sub..beta.-(1-naphthyl) A.sub..beta.-(1-naphthyl) (SEQ ID NO: 151);KWKAA.sub..beta.-(1-naphthyl) A.sub..beta.-(1-naphthyl) RFLKKWKAA.sub..beta.-(1-naphthyl) A.sub..beta.-(1-naphthyl) RFLK (SEQ ID NO: 152);KWKAA.sub..beta.-(1-naphthyl) A.sub..beta.-(1-naphthyl) RFLKKWKAA.sub..beta.-(1-naphthyl) A.sub..beta.-(1- (SEQ ID NO: 153);naphthyl) RFLKKWKAA.sub..beta.-(1-naphthyl) A.sub..beta.-(1-naphthyl)RFLKKA.sub..beta.-(1-naphthyl) KAQA.sub..beta.-(1-naphthyl) RFLKKA.sub..beta.-(1-naphthyl) KAQRFLK (SEQ ID NO: 156);KWKAQWRFLKKWKAQWRFL (SEQ ID NO: 159);KWKAA.sub..beta.-(1-naphthyl) KRFLKKWKAA.sub..beta.-(1-naphthyl) KRFLK (SEQ ID NO: 160);KA.sub..beta.-(1-naphthyl) KAQFRFLKKA.sub..beta.-(1-naphthyl) KAQFRFLK (SEQ ID NO: 161);KWKAQKRF (SEQ ID NO: 163);CKWKAQKRFLKMSC (SEQ ID NO: 164);CKWKAQKRFC (SEQ ID NO: 165);IKISGKWKAQKRA.sub..beta.-(1-naphthyl) LK (SEQ ID NO: 166);KWKAFFRFLKKWKAFFRFLK (SEQ ID NO: 101);IKISGKWKAAWRFLK (SEQ ID NO: 223);IKISGKWKAA.sub..beta.-(1-naphthyl) FRFLK (SEQ ID NO: 224);IKISGKWKAAFRFLK (SEQ ID NO: 225);andIKISGKWKAA.sub..beta.-(1-naphthyl) ARFLK (SEQ ID NO: 226).__________________________________________________________________________

3. A compound which is a peptide selected from the group consisting of:

______________________________________VHVHISKSKVGWLIQLFHKKIESALRNK (SEQ ID NO: 12);KSKVWLIQLFHKK (SEQ ID NO: 13);SVHVHISKSKVGWLIQLFHKKIESALRNK (SEQ ID NO: 14);KSKVGWLIQLFHKK (SEQ ID NO: 15);ASKVGWLIQLFHKK (SEQ ID NO: 33);KAKVGWLIQLFHKK (SEQ ID NO: 34);KSAVGWLIQLFHKK (SEQ ID NO: 35);KSKAGWLIQLFHKK (SEQ ID NO: 36);KSKVAWLIQLFHKK (SEQ ID NO: 37);KSKVGALIQLFHKK (SEQ ID NO: 38);KSKVGWAIQLFHKK (SEQ ID NO: 39);KSKVGWLAQLFHKK (SEQ ID NO: 40);KSKVGWLIALFHKK (SEQ ID NO: 41);KSKVGWLIQAFHKK (SEQ ID NO: 42);KSKVGWLIQLAHKK (SEQ ID NO: 43);KSKVGWLIQLFAKK (SEQ ID NO: 44);KSKVGWLIQLFHAK (SEQ ID NO: 45);KSKVGWLIQLFHKA (SEQ ID NO: 46);KSKVGWLIQLFHKKKSKVGWLIQLFHKK (SEQ ID NO: 56);GWLIQLFHKKIESALRNKMNS (SEQ ID NO: 61);VHVHISKSKVGWLIQLFHKKIE (SEQ ID NO: 67);KSKVGWLIQLWHKK (SEQ ID NO: 76);KSKVGA.sub..beta.-(1-naphthyl) LIQFHKK (SEQ ID NO: 77);KSKVLWLIQLFHKK (SEQ ID NO: 79);KSKVGWLILLFHKK (SEQ ID NO: 80);KSKVGWLIQLFLKK (SEQ ID NO: 81);KSKVGWLIFLFHKK (SEQ ID NO: 86);KSKVGWLIKLFHKK (SEQ ID NO: 87);KSKVGWLIQLFFKK (SEQ ID NO: 89);KSKVFWLIQLFHKK (SEQ ID NO: 90);KSKVGWLIQLFHKF (SEQ ID NO: 91);KSKVKWLIQLFHKK (SEQ ID NO: 92);KSKVKWLIKLFHKK (SEQ ID NO: 94);KSKVKWLIKLFFKFKSKVKWLIKLFFKF (SEQ ID NO: 95);KSKVGWLISLFHKK (SEQ ID NO: 103);KSKVGWLITLFHKK (SEQ ID NO: 105);KSKVGWLIQLFWKK (SEQ ID NO: 106);KSKVGWLIQLFHKW (SEQ ID NO: 107);KSKVGWLIQLA.sub..beta.-(1-naphthyl) HKK (SEQ ID NO: 108);KSKVGWLIQLFA.sub..beta.-(1-naphthyl) KK (SEQ ID NO: 109);KSKVGWLIQLFHKA.sub..beta.-(1-naphthyl) (SEQ ID NO: 110);KSKVGWLIQFFHKK (SEQ ID NO: 112);KSKVKA.sub..beta.-(1-naphthyl) LIQLFHKK (SEQ ID NO: 114);KSKVGW.sub.(p-amino) LIFLFHKK (SEQ ID NO: 119);KSKVKWLIQLWHKK (SEQ ID NO: 120);KSKVGWLUYLFHKK (SEQ ID NO: 121);KSKVGW.sub.D LIQLFHKK (SEQ ID NO: 122);KSKVGFLIQLFHKK (SEQ ID NO: 123);KSKVGF.sub.D LIQLPHKK (SEQ ID NO: 124);KSKVGA.sub.D-1-.beta.-(1-naphthyl) LIQLFHKK (SEQ ID NO: 125);KSKVGA.sub.2-.beta.-(1-naphthyl) LIQLFHKK (SEQ ID NO: 126);KSKVGA.sub.D-2-.beta.-(1-naphthyl) LIQLFHKK (SEQ ID NO: 127);KSKVGA.sub.(pyridyl) LIQLFHKK (SEQ ID NO: 128);KSKVGF.sub.(p-amino) LIQLFHKK (SEQ ID NO: 129);KSKVF.sub.(p-amino) WLIQLFHKK (SEQ ID NO: 130);KSKVGKLIQLPHKK (SEQ ID NO: 131);CKSKVGWLIQLFHKKC (SEQ ID NO: 133);KSKVKFLIQLFHKK (SEQ ID NO: 134);KSKVGYLIQLFHKK (SEQ ID NO: 135);KSKVGWLIQWFHKK (SEQ ID NO: 138);KSKVGWLIQA.sub..beta.-(1-naphthyl) FHKK (SEQ ID NO: 139);KSKVGA.sub.(cyclohexyl) LIQLFHKK (SEQ ID NO: 140);KSKVGWLIQLFA.sub..beta.-(1-naphthyl) KA.sub..beta.-(1-naphthyl) (SEQ ID NO: 142);KSKVGA.sub..beta.-(1-naphthyl) LIQLFA.sub..beta.-(1-naphthyl) KK (SEQ ID NO: 144);KSKVKALIQLFHKK (SEQ ID NO: 157);KSKVGVLIQLFHKK (SEQ ID NO: 162);KSKVGA.sub..beta.-(1-naphthyl) LIQLFHKK (SEQ ID NO: 167:KSKVGA.sub..beta.-(1-naphthyl) LIQA.sub..beta.-(1-naphthyl) FHKK (SEQ ID NO: 168);KSKVGA.sub..beta.-(1-naphthyl) LIF.sub.(p-amino) LFHKK (SEQ ID NO: 169);KSKVF.sub.(p-amino) A.sub..beta.-(1-naphthyl) LIQLFHKK (SEQ ID NO: 170);KSKVGA.sub..beta.-(1-naphthyl) LIQLWHKK (SEQ ID NO: 171);KSKVGWLIQA.sub..beta.-(1-naphthyl) FHKA.sub..beta.-(1-naphthyl) (SEQ ID NO: 172);KSKVGWLIA.sub..beta.-(1-naphthyl) LFHKA.sub..beta.-(1-naphthyl) (SEQ ID NO: 173);KSKVA.sub..beta.-(1-naphthyl) WLIQLFHKA.sub..beta.-(1-naphthyl) (SEQ ID NO: 174);KSKVGWLIQLWHKA.sub..beta.-(1-naphthyl) (SEQ ID NO: 175);KSKVGWLIQA.sub..beta.-(1-naphthyl) FA.sub..beta.-(1-naphthyl) KK (SEQ ID NO: 176);KSKVGWLIF.sub.(p-amino) LFA.sub..beta.-(1-naphthyl) KK (SEQ ID NO: 177);KSKVF.sub.(p-amino) WLIQLFA.sub..beta.-(1-naphthyl) KK (SEQ ID NO: 178);KSKVGWLIQLWA.sub..beta.-(1-naphthyl) KK (SEQ ID NO: 179);KSKVGWLIFL.sub.(p-amino) A.sub..beta.-(1-naphthyl) HKK (SEQ ID NO: 180);KSKVF.sub.(p-amino) WLIQA.sub..beta.-(1-naphthyl) FHKK (SEQ ID NO: 181);KSKVGWLIQA.sub..beta.-(1-naphthyl) WHKK (SEQ ID NO: 182);KSKVF.sub.(p-amino) WLIF.sub.(p-amino) LFHKK (SEQ ID NO: 183);KSKVGWLIF.sub.(p-amino) LWHKK (SEQ ID NO: 184);KSKVF.sub.(p-amino) WLIQLWHKK (SEQ ID NO: 185);KSKVGA.sub.D-.beta.-(2-naphthyl) LILLFHKK (SEQ ID NO: 190);KSKVGWLILLFHKKKSKVGWLILLFHKK (SEQ ID NO: 191);KSKVGWLIFLFHKKKSKVGWLIFLFHKK (SEQ ID NO: 192);KSKVGWLILLFHKKKSKVGWLIQLFHKK (SEQ ID NO: 193);KSKVGWLIQLFHKKKSKVGWLILLFHKK (SEQ ID NO: 194);KSKVGWLIFLFHKKKSKVGWLIQLFHKK (SEQ ID NO: 195);KSKVGWLIQLFHKKKSKVGWLIFLFHKK (SEQ ID NO: 196);KSKVGWLILLWHKK (SEQ ID NO: 198);KSKVGA.sub.D-.beta.-(2-naphthyl) LIQLWHKK (SEQ ID NO: 199);KSKVGA.sub.D-.beta.-(2-naphthyl) LILLWHKK (SEQ ID NO: 200);KSKVGGLIQLFHKK (SEQ ID NO: 201);KSKVGLLIQLFHKK (SEQ ID NO: 202);KSKVGWLIQLFHKK (SEQ ID NO: 203);KSKVGA.sub.D LIQLFHKK (SEQ ID NO: 204);KSKVGV.sub.D LIQLFHKK (SEQ ID NO: 205);KSKVGA.sub..beta. LIQLFHKK (SEQ ID NO: 206);KSKVG(delta-aminobutyric acid)LIQLFHKK (SEQ ID NO: 207);KSKVG(gamma-aminobutyric acid)LIQLFHKK (SEQ ID NO: 208);KSKVGA.sub.(delta-Methyl) LIQLFHKK (SEQ ID NO: 209);KSKVGG.sub.(t-butyl) LIQLFIJKK (SEQ ID NO: 210);KSKVGG.sub.(N-Methyl) LIQLFHKK (SEQ ID NO: 211);KSKVGV.sub.(N-Methyl) LIQLFHKK (SEQ ID NO: 212);KSKVGL.sub.(N-Methyl) LIQLFHKK (SEQ ID NO: 213);KSKVGWLINLFHKK (SEQ ID NO: 214);KSKVGWLIELFHKK (SEQ ID NO: 215);KSKVGWLIDLFHKK (SEQ ID NO: 216);KSKVGWLIKLFHKK (SEQ ID NO: 217);KSKVKVLIQLFHKK (SEQ ID NO: 218);KSKVKWAIQLFHKK (SEQ ID NO: 219);KSKVGVAIQLFHKK (SEQ ID NO: 220);andKSKVKVAIQLFHKK (SEQ ID NO: 221).______________________________________

4. A compound which is a peptide selected from the group consisting of:

__________________________________________________________________________KWKAQKRFLKKSKVGWLIQLFHKK (SEQ ID NO: 52);IKISGKWKAQKRFLKKSKVGWLIQLFHKK (SEQ ID NO: 53);KSKVGWLIQLFHKKKWKAQKRFLK (SEQ ID NO: 70);IKISGKA.sub..beta.-(1-naphthyl) KAQFRFLKKSKVGWLIFLFHKK (SEQ ID NO: 83);IKISGKA.sub..beta.-(1-naphthyl) KAQFRFLKKSKVGWLIQLFHKK (SEQ ID NO: 88);KWKAQFRFLKKSKVGWLILLFHKK (SEQ ID NO: 96);A.sub..beta.-(1-naphthyl) A.sub..beta.-(1-naphthyl) RFLKF (SEQ ID NO: 136);KWKAAARFLKKSKVGWLIQLFHKK (SEQ ID NO: 141);KWKVFKKIEKKSKVGWLIQLFHKK (SEQ ID NO: 147);IKISGKWKAA.sub..beta.-(1-naphthyl) A.sub..beta.-(1-naphthyl) RFLKKSKVGWLIQLFHKK (SEQ ID NO: 154);KA.sub..beta.-(1-naphthyl) KAQA.sub..beta.-(1-naphthyl) RFLKKSKVGKWKAFKRFLK (SEQ ID NO: 155);KWKAQWRFLKKSKVGWLIQLFHKK (SEQ ID NO: 158);KA.sub..beta.-(1-naphthyl) KAQA.sub..beta.-(1-naphthyl) RFLKKSKVGWLILLFHKK (SEQ ID NO: 186);KWKAQFRFLKKSKVGWLIQLWHKK (SEQ ID NO: 187);KWKAQFRFLKKSKVGA.sub.D-.beta.-(2-naphthyl) LIQLFHKK (SEQ ID NO: 188);KA.sub..beta.-(1-naphthyl) KAA.sub..beta.-(1-naphthyl) KRFLKKSKVGA.sub.D-.beta.-(2-naphthyl) LIQLFHKK (SEQ ID NO: 189);KWKAQFRFLKKSKVGWLIFLFHKK (SEQ ID NO: 197);andKA.sub..beta.-(1-naphthyl) AQFRFLKKSKVGWLILLFHKK (SEQ ID NO: 222).__________________________________________________________________________