US 5,652,332 A · 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.

Claims4

Dependent claims

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);
and GTAALQKELKRIKIP (SEQ ID NO:
5). ______________________________________

7 more elements

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..bet a.-(1-naphthyl) A.sub..beta.-(1-naphthyl) RFLK (SEQ ID NO:
152);
KWKAA.sub..beta.-(1-naphthyl) A.sub..beta.-(1-naphthyl) RFLKKWKAA.sub..bet a.-(1-naphthyl) A.sub..beta.-(1- (SEQ ID NO:
153);
naphthyl) RFLKKWKAA.sub..beta.-(1-naphthyl) A.sub..beta.-(1-naphthyl) RFLK KA.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);
and IKISGKWKAA.sub..beta.-(1-naphthyl) ARFLK (SEQ ID NO:
226). __________________________________________________________________________

159 more elements

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);
and KSKVKVAIQLFHKK (SEQ ID NO:
221). ______________________________________

229 more elements

Dependencies are inferred from the claim text.

Facts

Application

08/306,473Filed 15 Sep 1994 · continuation in part

Priority

12 Mar 1993

Granted

29 Jul 1997

Term ends

Not estimatedThe source records don’t support an estimate.

Classification4 codes

A61K 38/1751
From mammals: bactericidal/permeability-increasing protein [BPI]
C07K 14/4742
Not used: bactericidal/Permeability-increasing protein [BPI]
A61K
Medicines and medical preparations
C07K
Peptides

Family

Serial30,644Parent of this continuation-in-part · filed 12 Mar 1993

Serial93,202Parent of this continuation-in-part · filed 15 Jul 1993

Serial183,222Parent of this continuation-in-part · filed 14 Jan 1994

Serial209,762Parent of this continuation-in-part · filed 11 Mar 1994

US 5,348,942 AParent of this continuation-in-part

US 5,652,332 AThis patent

From the US filing history. Foreign family members aren’t listed.

Abstract

Facts

Application

08/306,473Filed 15 Sep 1994 · continuation in part

Priority

12 Mar 1993

Granted

29 Jul 1997

Term ends

Not estimatedThe source records don’t support an estimate.

Classification4 codes

A61K 38/1751
From mammals: bactericidal/permeability-increasing protein [BPI]
C07K 14/4742
Not used: bactericidal/Permeability-increasing protein [BPI]
A61K
Medicines and medical preparations
C07K
Peptides

Family

Serial30,644Parent of this continuation-in-part · filed 12 Mar 1993

Serial93,202Parent of this continuation-in-part · filed 15 Jul 1993

Serial183,222Parent of this continuation-in-part · filed 14 Jan 1994

Serial209,762Parent of this continuation-in-part · filed 11 Mar 1994

US 5,348,942 AParent of this continuation-in-part

US 5,652,332 AThis patent

From the US filing history. Foreign family members aren’t listed.

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

Life of this patent

Abstract

Claims4

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

Life of this patent

Abstract

Claims4