Histatins and method of use thereof

1. A synthetic histatin having the general structure:

[HTNF 1 -L 1 -HTNF 2 -(L 2 ) y ] x   (Formula I)

wherein

i) HTNF 1 is a first histatin fragment ranging in length from 5 to 20 amino acids;

ii) HTNF 2 is a second histatin fragment ranging in length from 5 to 20 amino acids;

iii) L 1 is a first linker;

iv) L 2 is a second linker;

v) x=1 to 3; and

vi) y=0 to 2;

wherein HTNF 1 and HTNF 2 are each independently the same or different and L 1 and L 2 are each independently the same or different, and

wherein at least one of HTNF 1 or HTNF 2 is HEXXH (SEQ ID NO: 2) or HEKRHH (SEQ ID NO:27), wherein each X is independently a basic amino acid residue,

and wherein when each of HTNF 1 and HTNF 2 is HEHKH (SEQ ID NO:50), x is 1 and y is 0.

2. The synthetic histatin of claim 1 , wherein HTNF 1 or HTNF 2 has an amino acid sequence of SNYLYDN (SEQ ID NO:1).

3. The synthetic histatin of claim 1 , wherein L 1 or L 2 is a flexible linker, rigid linker, in vivo cleavable linker, or a combination thereof.

4. The synthetic histatin of claim 3 , wherein the flexible linker is a hydrocarbon linker comprising 3 to 25 methylene groups.

5. The synthetic histatin of claim 4 , wherein the hydrocarbon linker has the structure —(CH 2 ) 6 —.

6. The synthetic histatin of claim 3 , wherein the flexible linker is a peptide linker having an amino acid sequence of (GGGGS) n (SEQ ID NO:3), KESGSVSSEQLAQFRSLD (SEQ ID NO:4), or EGKSSGSGSESKST (SEQ ID NO:5), GGGGGGGG (SEQ ID NO:6), GSAGSAAGSGEF (SEQ ID NO:7), (GGSG) n (SEQ ID NO:8), or (GS) n (SEQ ID NO:9), wherein n is 1, 2, 3, 4 or 5.

7. The synthetic histatin of claim 3 , wherein the rigid linker is a peptide linker having an amino acid sequence of (EAAAK) n (SEQ ID NO:10), A(EAAAK) n A (SEQ ID NO:11), PAPAP (SEQ ID NO:12), or (XP) n (SEQ ID NO:13), wherein n is 1, 2, 3, 4 or 5.

8. The synthetic histatin of claim 3 , wherein the in vivo cleavable linker is a peptide linker having an amino acid sequence of VSQTSKLTRAETVFPDV (SEQ ID NO:14), PLGLWA (SEQ ID NO:15), RVLAEA (SEQ ID NO:16), EDVVCCSMSY (SEQ ID NO:17), GGIEGRGS (SEQ ID NO:18), TRHRQPRGWE (SEQ ID NO:19), AGNRVRRSVG (SEQ ID NO:20), RRRRRRRRR (SEQ ID NO:21), GFLG (SEQ ID NO:22), or CRRRRRREAEAC (SEQ ID NO:23).

9. The synthetic histatin of claim 1 , wherein said synthetic histatin is linear or cyclized.

10. The synthetic histatin of claim 9 , wherein the synthetic histatin is cyclized via a disulfide bridge between terminal cysteine residues.

11. The synthetic histatin of claim 9 , wherein the synthetic histatin is cyclized with a sortase or butelase.

12. A synthetic histatin having the structure:

(a)

GYKRKFHEKHHSHR(SEQ ID NO: 24)-L 1 -YGDYGSNYLYDN(SEQ

ID NO: 25);

(b)

HEKHH(SEQ ID NO: 26)-L 1 -HEKHH(SEQ ID NO: 26)-

L 2 -HEKHH(SEQ ID NO: 26)-L 1 -YGDYGSNYLYDN(SEQ ID

NO: 25);

(c)

HEKRHH(SEQ ID NO: 27)-L 1 -HEKRHH(SEQ ID NO: 27)-

L 2 -HEKRHH(SEQ ID NO: 27)-L 1 -YGDYGSNYLYDN(SEQ ID

NO: 25);

(d)

HEKRHH(SEQ ID NO: 27)-L 1 -HEKRHH(SEQ ID NO: 27)-

L 2 -HEKHH(SEQ ID NO: 26)-L 1 -YGDYGSNYLYDN(SEQ ID

NO: 25);

or

(e)

HEKRHH(SEQ ID NO: 27)-L 1 -HEKHH(SEQ ID NO: 26)-

L 2 -HEKHH(SEQ ID NO: 26)-L 1 -YGDYGSNYLYDN(SEQ ID

NO: 25),

wherein each L 1 and L 2 is independently a flexible linker, rigid linker, or in vivo cleavable linker.

13. A synthetic histatin having the structure:

(a)

(SEQ ID NO: 28)

GYKRKEHEKHHSHR-(CH 2 ) 6 -YGDYGSNYLYDN;

(b)

(SEQ ID NO: 29)

HEKHH-(CH 2 ) 6 -HEKHH-(CH 2 ) 6 -HEKHH-(CH 2 ) 6 -

YGDYGSNYLYDN;

(c)

(SEQ ID NO: 30)

HEKRHH-(CH 2 ) 6 -HEKRHH-(CH 2 ) 6 -HEKRHH-(CH 2 ) 6 -

YGDYGSNYLYDN;

(d)

(SEQ ID NO: 31)

HEKRHH-(CH 2 ) 6 -HEKRHH-(CH 2 ) 6 -HEKHH-(CH 2 ) 6 -

YGDYGSNYLYDN;

or

(e)

(SEQ ID NO: 32)

HEKRHH-(CH 2 ) 6 -HEKHH-(CH 2 ) 6 -HEKHH-(CH 2 ) 6 -

YGDYGSNYLYDN.

14. A composition comprising one or more synthetic histatins of claim 1 and a pharmaceutically acceptable carrier or excipient.

15. The composition of claim 14 , wherein said composition is formulated for ocular administration.

16. A kit comprising one or more synthetic histatins of claim 1 .

17. A synthetic histatin having the general structure:

[HTNF 1 -L 1 -HTNF 2 -(L 2 ) y ] x   (Formula I)

wherein

i) HTNF 1 is a first histatin fragment ranging in length from 5 to 20 amino acids;

ii) HTNF 2 is a second histatin fragment ranging in length from 5 to 20 amino acids;

iii) L 1 is a first linker;

iv) L 2 is a second linker;

v) x=1 to 3; and

vi) y=0 to 2;

wherein

HTNF 1 and HTNF 2 are each independently the same or different, L 1 and L 2 are each independently the same or different, and at least one of L 1 or L 2 is a hydrocarbon linker comprising 3 to 25 methylene groups.

18. A synthetic histatin having the general structure:

[HTNF 1 -L 1 -HTNF 2 -(L 2 ) y ] x   (Formula I)

wherein

i) HTNF 1 is a first histatin fragment ranging in length from 5 to 20 amino acids;

ii) HTNF 2 is a second histatin fragment ranging in length from 5 to 20 amino acids;

iii) L 1 is a first linker;

iv) L 2 is a second linker;

v) x=1 to 3; and

vi) y=0 to 2;

wherein

HTNF 1 and HTNF 2 are each independently the same or different;

at least one of HTNF 1 or HTNF 2 comprises SNYLYDN (SEQ ID NO:1) or HEXXH (SEQ ID NO:2), wherein each X is independently a basic amino acid residue;

L 1 and L 2 are each independently the same or different; and

at least one of L 1 or L 2 is a hydrocarbon linker comprising 3 to 25 methylene groups.