WO2008050830A1 - Anti-hiv agent - Google Patents

Abstract

Disclosed are: a polypeptide having excellent anti-HIV activity, which is produced by modifying an amino acid sequence corresponding to HR2 region of HIV; an anti-HIV agent comprising the polypeptide as an active ingredient; a pharmaceutical composition comprising the anti-HIV agent; a method for treating HIV by using the anti-HIV agent; and others.

Description

 Specification

 Anti-HIV agent

 Technical field

 [0001] The present invention relates to a peptide having an excellent membrane fusion inhibitory action against HIV, and use of the peptide for prevention or treatment of AIDS virus-related diseases. Background art

 [0002] AIDS (Acquired Immuno Deficiency Syndrome) is an abbreviation for acquired immune deficiency syndrome, and normal immunity against pathogens is obtained by infection with retroviruses that cause immunodeficiency (eg, HIV, SIV). It is a collective term for various diseases that develop when people stop working.

 [0003] As one of the mechanisms by which retroviruses that cause immunodeficiency, such as HIV, enter the host cell, the C34 trimer with α-helical structure in HIV gp41 protein has a single helix structure. A mechanism is known in which a hexamer is formed so as to wrap around a trimer of HR1, and fusion between the cell membrane of HIV and the cell membrane of the host cell occurs (see, for example, Non-Patent Document 1). Drugs that target HR1 and prevent the formation of the above hexamer, such as T20 (trade name Fuzeon: polypeptide shown in SEQ ID NO: 3), are approved by the US FDA. -The presence of vermilion has already been confirmed (see, for example, Non-Patent Document 2), and a drug with further anti-HIV activity is needed

Yes

 Non-patent literature l: Reviw: D.M.Eckert, P.S.Kim, Annu. Rev. Biochem. 2001, 70, 777-81 0

 Non-Patent Document 2: Xu, et. Al., ANTIMICROBIAL AGENT AND CHEMOTHERAPY, Mar, 2005, 49, 1113-1119

 Disclosure of the invention

 Problems to be solved by the invention

[0004] The present invention includes a polypeptide capable of binding to HIV gp41 HR1 and inhibiting fusion of HIV cell membrane and host cell cell membrane, an anti-HIV agent comprising the polypeptide as an active ingredient, and the anti-HIV agent. The main object of the present invention is to provide a pharmaceutical composition having the same and a method for treating HIV using the anti-HIV agent.

 Means for solving the problem

 [0005] As clarified by Non-Patent Document 2, resistance to T20 is considered to be caused by amino acid mutations in the HR1 region and HR2 region of gp41. This is considered to have an effect of reducing the affinity for T20 having inhibitory activity as a partial peptide of the HR2 region. On the other hand, the amino acid mutation in the HR2 region forms an HR2 region having a higher affinity than T20, and is considered to be able to maintain a high affinity for the sequence of the HR1 region after the mutation. Such mutations in the HR1 region and HR2 region can be said to be a purpose for obtaining virus resistance.

 [0006] The present inventors pay attention to the mechanism of acquiring resistance of this virus, and if a membrane fusion inhibitor peptide is designed in accordance with the amino acid sequence of the HR2 region of the T20 resistant strain, high activity against the resistant strain is achieved. It was expected that peptides having high activity against wild type viruses would be found.

 [0007] By the way, amino acid mutations in viruses are caused by mutations in DNA bases encoding amino acids, and mutations from specific amino acids are limited to several types of natural amino acids. However, synthetic chemistry is not limited to mutations in viruses, and it is possible to prepare peptides into which any amino acid is commercially available as a chemical reagent. Thus, the present inventors comprehensively synthesized derivatives of HR2 peptides in which the amino acid substitution positions occurring at the contact sites of the HR2 region with the HR1 region were converted to various amino acids, and developed these antiviral products. When the activity was evaluated, it was found that the membrane fusion inhibitory effect of wild-type strains and HIV-resistant strains, including T20-resistant strains, and host cells was dramatically enhanced.

[0008] In addition, as a peptide that binds to N36 including HR1, for example, as described in JP-A-2003-176298, it has a plurality of modular structures consisting of 6 or 7 amino acids, By combining the amino acid at position i and position i + 4 with acidic amino acid and basic amino acid (or vice versa), a salt bridge is formed between the two, making it easier to form an α-Rix. Things. [0009] With reference to such findings, the present inventors changed the amino acid of T20 to acidic amino acid (X), base

 A

 Module for regular substitution with a functional amino acid (X) (X-X X -XX-X X or X-

B A A B B

X X -XX-X X, where X represents an amino acid not substituted for T20)

B B A A

 Got a variant.

 [0010] Although not intended to be a limited interpretation of the present invention, one, two or three of the peptides of the present invention obtained in this way are the three HR1 regions of HIV gp41. It is thought to form a complex, inhibit membrane fusion between HIV and the host, and prevent HIV infection.

 [0011] The present invention provides the following polypeptides, anti-HIV agents and pharmaceutical compositions containing the anti-HIV agents.

 Item 1. A polypeptide containing amino acids in the order shown in Table I below (SEQ ID NO: ι).

 [0012] [Table 1]

 Table I

(In Table I, x represents serine, alanine, glycine, isoleucine, leucine, methionine, threo.

 1

 Any force selected from the group consisting of nin and valine, representing one amino acid;

 R is an amino acid sequence represented by SEQ ID NO: 4, lj, a variant thereof and a group consisting of an acyl group

1

 Represents V selected, one of them;

 R represents at least one selected from the group consisting of the amino acid sequence represented by SEQ ID NO: 6, a variant thereof, an amino group and an amino group having a substituent;

 X is tyrosine,

 Tyr

 X is Thread Nin,

 Thr

X is serine, X

 EU

 X

 I]

 X

 His

 X is glutamic acid,

 Glu

 X is glutamine,

 Gin

 X is asparagine,

 Asn

 X is lysine,

 Ys

 X is aspartic acid,

 Asp

 X and X are tryptophan,

 Trpl Trp2

 X is alanine,

 Ala

 X is phenylenolanine;

 Phe

 In addition, 1 to 3 amino acids in Table I may be substituted according to the following rules (i) to (xv).

 (0 X is the same or different and is due to a single base mutation from the codon encoding tyrosine.

Tyr

At least one selected from the group consisting of the resulting amino acids, one species;

 (ii) X is the same or different and represents a single base mutation from the codon encoding threonine.

Thr

Thus at least one force selected from the group consisting of the resulting amino acids, one species;

 (iii) X is the same or different and is due to a single base mutation from the codon encoding serine.

Ser

At least one force selected from the group consisting of the amino acids generated by

 (iv) X is the same or different, and eu is due to a single base mutation from the codon encoding leucine.

At least one selected from the group consisting of the resulting amino acids, one species;

 (V) X is the same or different and a single base mutation from the codon encoding isoleucine

He

At least one force selected from the group consisting of amino acids generated by

 (vi) X is the same or different and is a single base mutation from the codon encoding histidine.

His

Thus at least one force selected from the group consisting of the resulting amino acids, one species;

 (vii) X is the same or different and is a single base change from the codon encoding glutamate.

Glu

At least one force selected from the group consisting of different amino acids, one species;

(viii) X is the same or different, and a single base mutation from the codon encoding glutamine At least one force selected from the group consisting of amino acids generated by

 (ix) X is the same or different and is a single base change from the codon encoding asparagine.

Asn

At least one force selected from the group consisting of different amino acids, one species;

 (X) X is the same or different and is a single base mutation from the codon encoding lysine.

At least one force selected from the group consisting of the amino acids generated by

 (xi) X is the same or different and is a single base from the codon encoding aspartic acid.

Asp

At least one force selected from the group consisting of amino acids generated by mutation, one species;

 (xii) X is the same or different and is a single base change from the codon encoding tryptophan.

Trpl

At least one force selected from the group consisting of different amino acids, one species;

 (xiii) X is the same or different and is a single base change from the codon encoding tryptophan.

Trp2

At least one selected from the group consisting of amino acids and alanine which are caused by different;

 (xiv) X is the same or different and represents a single base mutation from the codon encoding alanine.

Ala

Thus at least one force selected from the group consisting of the resulting amino acids, one species;

 (XV) X is the same or different, one base from the codon encoding phenylalanin

Phe

And at least one selected from the group consisting of amino acids and alanine produced by mutation of

 Furthermore, the amino acids of B 歹 IJ, C 歹 IJ, F column and G column may be substituted according to the following rule (xvi).

 (xvi) in Table I;! -6 rows, 2 amino acids in columns B and C in the same row, and 2 amino acid forces in columns F and G, respectively,

 Is at least one acidic amino acid selected from the group consisting of glutamic acid, aspartic acid, and cysteic acid.

 It is the same or different and is at least one force selected from the group consisting of lysine, arginine, ornithine and histidine, and one basic amino acid.

 Here, in the same row, when the two amino acids in columns B and C are acidic amino acids, the two amino acids in columns F and G are basic amino acids,

When two amino acids in row B and C are basic amino acids, two amino acids in row F and G Noic acid is an acidic amino acid;

 In addition, the amino acids shown in Table I are bound in the following order with R as the N-terminus.

 1

 R -1D-1E-1F-1G-2A-2B-2C-2D-2E-2F-2G-3A-3B-3C-3D-3E-3F-3G-4A-4B-4

1

 C-4D-4E-4F-4G-5A-5B-5C-5D-5E-5F-5G-6A-6B-6C-6D-R

 However, 1D-1E-1F-1G is missing from the N-terminal side in order! /, May! / ヽ;

 Also, if no amino acid other than X is substituted, X is not serine).

 1 1

Item 2. In Table I above

 X

 X is threaded

 Thr

X is serine,

 X X

 X is glutamic acid,

 Glu

 X is gnoretamine,

 Gin

 X is Asparagine,

 Asn

 X force s lysine,

 Ys

 X is aspartic acid,

 Asp

 X and X force S tryptophan,

 Trpl Trp2

 X is alanine,

 Ala

 Item 2. The polypeptide according to Item 1, wherein X is phenylalanin.

 Phe

Item 3 · In Table I above, X force alanine, glycine, isoleucine, leucine, methionine

 1

 Item 3. The polypeptide according to Item 1 or 2, which is either threonine or parin.

Item 4.

 And X is alanine, glycine, isoleucine, leucine, methionine, threonine or

 1

One of the phosphorus,

Item 4. The polypeptide according to any one of Items 1 to 3, wherein R is a acetyl group and R is -ΝΗ. Item 5. A polypeptide containing amino acids in the order shown in Table II below (SEQ ID NO: 2).

[Table 2]

Table II

(In Table II, R represents an amino acid sequence IJ represented by SEQ ID NO: 13, a modified form thereof, and an acyl group.

 Three

V represents one selected from the group consisting of:

 R has the amino acid sequence represented by SEQ ID NO: 15, a variant thereof, an amino group, and a substituent.

Four

Represents at least one force selected from the group consisting of amino groups;

 X is leucine,

 EU

 X is aspartic acid,

 Asp

 X is alanine,

 Ala

 X is asparagine,

 Asn

 X is isoleucine,

 lie

 X is threonine,

 Thr

 X is lysine,

 Ys

 X is glutamic acid,

 Glu

 X is glutamine,

 Gin

 X is methionine,

 Met

 X is tyrosine,

 Tyr

 X is tryptophan,

 Trp

 X is serine,

 Ser

X is phenylenolanine; In addition, 1 to 3 amino acids in Table II may be substituted according to the following rules (i) to (xiv).

 (0 X is the same or different and eu is due to a single base mutation from the codon encoding leucine.

At least one selected from the group consisting of the resulting amino acids, one species;

 (ii) X is the same or different and is a single base change from the codon encoding aspartic acid.

Asp

At least one force selected from the group consisting of different amino acids, one species;

 (iii) X is the same or different and is due to a single base mutation from the codon encoding alanine.

Ala

At least one selected from the group consisting of the resulting amino acids, one species;

 (iv) X is the same or different and is a single base change from the codon encoding asparagine.

Asn

At least one force selected from the group consisting of different amino acids, one species;

 (V) X is the same or different and is a single base mutation from the codon encoding isoleucine.

At least one force selected from the group consisting of amino acids generated by

 (vi) X is the same or different and is a single base mutation from the codon encoding threonine.

Thr

At least one force selected from the group consisting of amino acids generated by

 (vii) X is the same or different and ys is due to a single base mutation from the codon encoding lysine.

At least one selected from the group consisting of the resulting amino acids, one species;

 (viii) X is the same or different and is a single base change from the codon encoding glutamate.

Glu

At least one force selected from the group consisting of different amino acids, one species;

 (ix) X is the same or different and is a single base mutation from the codon encoding glutamine.

Gin

Thus at least one force selected from the group consisting of the resulting amino acids, one species;

 (X) X is the same or different and is a single base mutation from the codon encoding methionine

Met

At least one force selected from the group consisting of amino acids generated by

 (xi) X is the same or different and is a single base mutation from the codon encoding tyrosine.

Tyr

Thus at least one force selected from the group consisting of the resulting amino acids, one species;

 (xii) X is the same or different and is a single base change from the codon encoding tryptophan.

Trp

At least one force selected from the group consisting of different amino acids, one species;

 (xiii) X is the same or different and is due to a single base mutation from the codon encoding serine.

Ser

At least one selected from the group consisting of the resulting amino acids, one species; (xiv) X is the same or different and is a single base from the codon encoding phenylalanin.

Phe

It is at least one selected from the group consisting of amino acids generated by mutations in B, and even if B さ ら に IJ, C 歹 IJ, F column and G column amino acids are substituted according to the rule of (XV) below Good.

 (XV) In Table II;! ~ 6 rows, two amino acids in columns B and C in the same row, and two amino acid forces in columns F and G, respectively,

 Is at least one acidic amino acid selected from the group consisting of glutamic acid, aspartic acid, and cysteic acid.

 It is the same or different and is at least one force selected from the group consisting of lysine, arginine, ornithine and histidine, and one basic amino acid.

 Here, in the same row, when the two amino acids in columns B and C are acidic amino acids, the two amino acids in columns F and G are basic amino acids,

 When the two amino acids in columns B and C are basic amino acids, the two amino acids in columns F and G are acidic amino acids;

 The amino acids shown in Table II are bound in the following order, with R as the N-terminus.

 Three

 R -1D-1E-1F-1G-2A-2B-2C-2D-2E-2F-2G-3A-3B-3C-3D-3E-3F-3G-4A-4B-4

Three

 C-4D-4E-4F-4G-5A-5B-5C-5D-5E-5F-5G-6A-6B-6C-6D-R

 Four

 However, 1D-1E-1F-1G is missing in order from the N-terminal side! /, May! /)).

Item 6. In Table II above

 X is leucine,

 EU

 X is aspartic acid,

 Asp

 X is alanine,

 Ala

 X is asparagine,

 Asn

 X is isoleucine,

 lie

 X is threonine,

 Thr

 X is lysine,

 Ys

X is glutamic acid, X is glutamine,

 Gin

 X is methionine,

 Met

 X is tyrosine,

 Tyr

 X is tryptophan,

 Trp

 X is serine,

 Ser

 Item 6. The polypeptide according to Item 5, wherein X is phenylenolanine.

 Phe

Item 7.In Table II, the amino acids in columns B and C are glutamic acid, the amino acids in columns F and G are lysine,

 Item 7. The polypeptide according to Item 5 or 6, wherein R is a acetyl group, and R is -NH.

 3 4 2

Item 8 · The polypeptide according to any one of Items 1 to 4, which has an amino acid sequence of any one of (a) to (f) below:

 (a Tyr_Thr_Ser_Leu_Ile_His_Ser_Leu_Ile_Glu_Glu_Ala_Gin_Asn_Gln_Gin_Glu_Lys _Asn_Glu_Gln_Glu_L u_L u_Glu_L u_Asp_Lys_Trp_ u_Trp_ u

 (WTyr_Thr_Ser_Leu_ne_His_Ser_Leu_Ile_Glu_Glu_Ile_Gln_Asn_Gln_Gln_Glu_Lys _Asn_Glu_Gln_Glu_L u_L u_Glu_L u_Asp_Lys_Trp_Ala ~ S r_n_T_rp_T_rp_T

 (c) Tyr_Thr_Ser_Leu_ne_His_Ser_Leu_Ile_Glu_Glu_Leu_Gln_Asn_Gln_Gln_Glu_Ly s_Asn_Glu_Gln_Giu_L u_L u_Glu_L u_Asp_Lys_Trp_ u_Trp_u

 (d) Tyr_Thr_Ser_Leu_ne_His_Ser_Leu_Ile_Glu_Glu_Met_Gln_Asn_Gln_Gln_Glu_Ly s_Asn_Glu_Gln_Giu_L u_L u_Glu_L u_Asp_Lys_Trp_ u_Trp_ u

 (e) Tyr_Thr_Ser_Leu_Ile_His_Ser_Leu_Ile_Glu_Glu_Thr_Gln_Asn_Gln_Gln_Glu_Ly s_Asn_Glu_Gln_Glu_L u_L u_Glu_L u_Asp_Lys_Trp_Lla_P

(f) Tyr_Thr_Ser_Leu_Ile_His_Ser_Leu_Ile_Glu_Glu_Val_Gln_Asn_Gln_Gln_Glu_Lys _Asn_Glu_Gln_Glu_L u_L u_Glu_L u_Asp_Lys_Trp_Ala_Trp_L Phe (SEQ ID NO: 22)

Item 9. The polypeptide according to any one of Items 1 to 4, having the amino acid sequence of any one of (g) to (v) below.

 (g) Tyr_Thr_Ser_Leu- Ile_Glu_Glu_Leu- Ile_Lys_Lys_Ser_Glu_Glu_Gln_Gln_Lys_Lys _Asn_Glu_Glu_Glu_Leu_Lys_Lys_Leu_Giu_Glu_Trp_AlaTrp_ys

 (h) Tyr_Thr_Ser_Leu_ne_Glu_Glu_Leu_Ile_Lys_Lys_Ala_Glu_Giu_Gln_Gln_Lys_Ly s-Asn-Glu-Glu-Glu-Leu-Lys-Lys-Leu-Glu-Glu-Trp-Ala-Lrp-ys-Trp-Ala-Lrp-ys

 (i) Tyr_Thr_Ser_Leu_ne_Glu_Glu_Leu_Ile_Lys_Lys_Gly_Glu_Glu_Gln_Gln_Lys_Lys _Asn_Glu_Glu_Glu_Leu_Lys_Lys_Leu_Glu_Glu_Trp_Ala_Lrp_ys_T__

 (j) Tyr_Thr_Ser_Leu_ne_Glu_Glu_Leu_ne_Lys_Lys_Ile_Glu_Glu_Gln_Gln_Lys_Lys_ Asn_Glu_Glu_Glu_Leu_Lys_Lys_Leu_Glu_Glu_Trp_Ala_Lys_hysTrp_T

 (k) Tyr_Thr_Ser_Leu_Ile_Glu_Glu_Leu_Ile_Lys_Lys_Leu_Glu_Glu_Gln_Gln_Lys_Ly s-Asn-Glu-Glu-Glu-Leu-Lys-Lys-Leu-Glu-Glu-Trp-Lla-Trp-L

 (l) Tyr_Thr_Ser_Leu_ne_Glu_Glu_Leu_Ile_Lys_Lys_Met_Glu_Glu_Gln_Gln_Lys_Ly s-Asn-Glu-Glu-Glu-Leu-Lys-Lys-Leu-Glu-Glu-Trp-Ala-Lrp-ys-Trp-Ala-Lrp-ys

 (m) Tyr_Thr_Ser_Leu_Ile_Glu_Glu_Leu_Ile_Lys_Lys_Thr_Glu_Glu_Gln_Gln_Lys_Ly s-Asn-Glu-Glu-Glu-Leu-Lys-Lys-Leu-Glu-Glu-Trp-Lla-Trp-L

 (n) Tyr_Thr_Ser_Leu_ne_Glu_Glu_Leu_Ile_Lys_Lys_Vai_Glu_Glu_Gln_Gln_Lys_Ly s-Asn-Glu-Glu-Glu-Leu-Lys-Lys-Leu-Glu-Glu-Trp-Ala-Lrp-ys-Trp-Ala-Lrp-ys

(o) Ile_Glu_Glu_Leu- Ile_Lys_Lys_Ser_Glu_Glu_Gln_Gln_Lys_Lys_Asn_Glu_Glu_Gl u-Leu-Lys-Lys-Leu-Glu-Glu-Trp-Ala-Lys-Lys-Trp-Asn-Trp-Phe (Rooster himself 歹 lj number 31) (p) Tyr_Thr_Ser_Leu_ne_Glu_Glu_Leu_Ile_Lys_Lys_Ser_Glu_Glu_Gln_Gln_Lys_Ly s_Asn_Glu_Glu_Glu_Leu_Lys_Lys_Leu_Glu_Glu_Ala_Ala_Lys_Lys_Trp_Asn_Trp_ Phe (SEQ ID NO: 32)

 (q) Tyr_Thr_Ser_Leu_ne_Glu_Glu_Leu_Ile_Lys_Lys_Ser_Glu_Glu_Gln_Gln_Lys_Ly s_Asn_Glu_Glu_Glu_Leu_Lys_Lys_Leu_Glu_Glu_Trp_AlaT

 (r) Tyr_Thr_Ser_Leu- Ile_Glu_Glu_Leu- Ile_Lys_Lys_Ser_Glu_Glu_Gln_Gln_Lys_Lys _Asn_Glu_Glu_Glu_Leu_Lys_Lys_Leu_Glu_Glu_Trp_AlaTrp_ys_Lrp_A

 (s) Tyr_Thr_Ser_Leu- Ile_Lys_Lys_Leu- Ile_Glu_Glu_Ser_Lys_Lys_Gln_Gln_Glu_Glu _Asn_Glu_Glu_Glu_Leu_Lys_Lys_Leu_Glu_Glu_Trp_AlaTrp_ys

 (t) Tyr_Thr_Ser_Leu- Ile_Glu_Glu_Leu- Ile_Lys_Lys_Ser_Lys_Lys_Gln_Gln_Glu_Glu _Asn_Lys_Lys_Glu_Leu_Glu_Glu_Leu_Glu_Glu_Trp_AlaTrp_Lrp_H

 (u) Tyr_Thr_Ser_Leu_ne_Glu_Glu_Leu_Ile_Lys_Lys_Ser_Lys_Lys_Gln_Gln_Glu_Gl u_Asn_Glu_Glu_Glu_Leu_Lys_Lys_Leu_Lys_Lys_Trp_Ala_Trp_lu_he

 (v) Tyr_Thr_Ser_Leu- Ile_Lys_Lys_Leu- Ile_Glu_Glu_Ser_Glu_Glu_Gln_Gln_Lys_Lys _Asn_Glu_Glu_Glu_Leu_Lys_Lys_Leu_Lys_Lys_Trp_AlaTrp_lu_p

Item 10. The polypeptide according to any one of Items 5 to 7, which has an amino acid sequence of either (w) or (x) below.

 (w) Leu_Asp_Ala_Asn_Ile_Thr_Lys_Leu_Leu_Glu_Glu_Ala_Gln_Ile_Gln_Gln_Glu_L ys_Asn_Met_Tyr_Glu_Leu_Gln_Lys_Leu_Asn_Gln_Trp_hepT

(x) Leu_Asp_Ala_Asn_ne_Glu_Glu_Leu_Leu_Lys_Lys_Ala_Glu_Glu_Gln_Gln_Lys_L ys_Asn_Glu_Glu_Glu_Leu_Lys_Lys_Leu_Glu_Glu_Trp_Asp_Lys_Lys_Ser_Asn_Trp -Phe (SEQ ID NO: 40)

 Item 11. An anti-HIV agent comprising as an active ingredient the polypeptide according to Item 1 to 10 or!, Or a pharmaceutically acceptable salt thereof.

 Item 12. A pharmaceutical composition comprising the anti-HIV agent according to Item 11 together with a pharmaceutically acceptable carrier or additive.

Claim 13. Anti-HIV agent according to the polypeptide or claim 11 comprising contained so that a pharmaceutically acceptable 0.01 ₈ to 10 mg 1 day 1 kg body weight per against salt force adults.

 Item 14. A method for treating HIV, comprising administering an effective amount of the polypeptide according to any one of Items 1 to 10 to an HIV patient.

 Item 15. Use of the polypeptide according to claim 10 for producing a composition for treating HIV.

 The invention's effect

 [0016] The polypeptide of the present invention interacts with HIV gp41 HR1 to inhibit fusion of HIV cell membrane and host cell cell membrane, thereby inhibiting HIV infection. The polypeptide of the present invention can exhibit an excellent anti-HIV activity with a higher affinity for HR1 than T20, which has been conventionally used as an anti-HIV agent. In addition, the polypeptide of the present invention can effectively act against HIV, a resistant strain of T20.

 [0017] T20 is known to have anti-HIV activity against HIV-Z, and the polypeptide of the present invention can effectively act on, for example, the HIV-2 strain. Therefore, according to the polypeptide of the present invention, it can be used for the prevention or treatment of HIV infection against a wide variety of HIV.

 [0018] Furthermore, according to the present invention, there are also provided an anti-HIV agent effective for preventing or treating HIV infection, and a pharmaceutical composition containing the anti-HIV agent, comprising such a polypeptide as an active ingredient. be able to.

 BEST MODE FOR CARRYING OUT THE INVENTION

Hereinafter, the polypeptide of the present invention, an anti-HIV agent containing the polypeptide as an active ingredient, and a pharmaceutical composition containing the HIV agent will be described. [0020] 1. Polypeptide having anti-HIV activity

 The present invention provides polypeptides shown as the following variant I and variant II.

[0021] [Variant I]

 The present invention provides, as variant I, a polypeptide that has been modified based on the amino acid sequence of the HR2 region of the HIV-1 NL4-3 strain (SEQ ID NO: 3). In the present invention, variant I is a polypeptide comprising amino acids in the order shown in Table I below.

[0022] [Table 3]

 Table I

lVpl Asn lVp2 Xphe- ₂

[0023] In Table I, X represents serine, alanine, glycine, isoleucine, leucine, methionine, threo

 1

 Any one force selected from the group consisting of nin and parin represents one amino acid, preferably serine, alanine, isoleucine, leucine or methionine, more preferably alanine, isoleucine or methionine. However, amino acids other than X are the following (i) to (xvi)

 1

 If not substituted according to X is not serine.

 1

 [0024] R is an amino acid sequence located at 117-126 of the gp41 HR2 region of HIV-1 (Trp-Met-Glu-

1

 Trp-Asp-Arg-Glu-Ile-Asn-Asn: SEQ ID NO: 4), a variant thereof and a group force consisting of a acyl group. At least one selected force represents one kind.

[0025] A variant of the amino acid sequence represented by SEQ ID NO: 4 is X -X -X -X -X -X -X-

Trp Met Glu Trp Asp Arg Glu

An amino acid is substituted according to the following rule of ~ (xvi) expressed as X -X -X lie Asn Asn

 Modified variants. Preferably, the amino acids corresponding to the B and C columns are dartamic acid, and the amino acids corresponding to the F and G columns are lysine. That is, X -Glu-Glu

 Trp

—X —X -Lys-Lys-X -Glu-Glu (SEQ ID NO: 5) [0026] Met (methionine) of R is an amino acid generated by a single base mutation from a codon encoding methionine, that is, at least selected from the group consisting of leucine, valine, isoleucine, threonine, lysine and arginine. , It is replaced by one or more kinds,

[0027] Ar of Ar (arginine) is an amino acid generated by a single base mutation from the codon encoding arginine, that is, leucine, proline, histidine, glutamine, cysteine tryptophan, serine, glycine, isoleucine, methionine, Substituted with at least one selected from the group consisting of threonine and lysine!

 [0028] When R is an asinole group, the amino terminal N-terminal of the 1D (D column 1st row), 1E, 1F, 1G or 2A amino acid represented in Table I above is Acetyl groups such as acetyl group, propionyl group, butyryl group, benzoyl group, benzyloxycarbonyl group, phthalyl group, honoleminole group, triphenoloacetyl group, benzyl group, etc. may be bonded, preferably acetyl group, propionyl group. A butyryl group, a benzoyl group, a phthalinole group, a honoreminole group, and a trifnoreo mouth acetyl group, more preferably a acetyl group.

 [0029] R is an amino acid sequence (Asn-Ile-Thr-Asn-Trp-Leu-Trp-Tyr-Ile-Lys: SEQ ID NO: 6) of HIV gp41, a variant thereof, an amino group and It represents at least one force selected from the group consisting of an amino group having a substituent.

 [0030] The amino acid sequence variant represented by SEQ ID NO: 6 is X -X -X -X -X -X -X-

Examples thereof include a variant represented by X 1 -X 2 -X, in which an amino acid is substituted according to the following rule (1) to (xvi). Preferably, the amino acids corresponding to the B and C columns are dartamic acid, and the amino acids corresponding to the F and G columns are lysine. That is, X -Lys-Lys

-X -Glu-Glu-X -X -Lys-Lys (SEQ ID NO: 7)

 [0031] When R is an amino group or an amino group having a substituent, X at the 6D position represented in Table I above

 An amino group such as -NH, methylamino group, dimethylamino group, ethylamino group, jetylamino group, benzylamino group or the like may be bonded to the C-terminal carbonyl group of -NH, methylamino group, dimethylamino group, An ethylamino group or a jetylamino group is bonded, and more preferably —NH is bonded.

In the present invention, it is more preferable that R is a acetyl group and R is —NH. [0033] In Table I, amino acids are defined as follows.

[0034] X

 X is a thread

 Thr

X is serine,

 X X

 X is glutamic acid,

 Glu

 X is glutamine,

 Gin

 X is asparagine,

 Asn

 X is lysine,

 Ys

 X is aspartic acid,

 Asp

 X and X are tryptophan,

 Trpl Trp2

 X is alanine,

 Ala

 X is phenylenolanine.

 Phe

 [0035] In the present invention, 1 to 3 amino acids of the amino acids shown in Table I are substituted according to the following rules (i) to (xv)!

 [0036] (0 X is the same or different and is due to a single base mutation from the codon encoding tyrosine.

 Tyr

 There is at least one force selected from the group consisting of the resulting amino acids, ie, phenylenolanine, serine, cysteine, histidine, wasparagine and aspartic acid.

 [0037] (ii) X is the same or different and is a single base mutation from the codon encoding threonine.

 Thr

 Thus, the resulting amino acid is at least one selected from the group consisting of isoleucine, methynin, asparagine, lysine, serine, arginine, proline and alanine.

 [0038] (iii) X is the same or different, and is caused by a single base mutation from the codon encoding serine.

 Ser

Resulting amino acids such as phenylalanine, leucine, tyrosine, cysteine, tryptophan, proline, thread nin, alanine, isoleucine, asparagine, anoleginin, glycine At least one force selected from the group consisting of thin and cysteine.

[0039] (iv) X is the same or different and is due to a single base mutation from the codon encoding leucine.

 EU

 And at least one selected from the group consisting of proline, histidine, glutamine, arginine, phenylalanine, isoleucine, methionine, Norin, serine and tryptophan.

[0040] (V) X is the same or different and is a single base mutation from the codon encoding isoleucine

 lie

 Or at least one selected from the group consisting of threonine, asparagine, lysine, serine, arginine, phenylalanine, leucine, methionine, and parin.

[Vi] (vi) X is the same or different and is a single-base mutation from the codon encoding histidine.

 His

 Thus, at least one force selected from the group consisting of leucine, proline, anoleginin, tyrosine, asparagine, glutamine and aspartic acid, one kind [0042] (vii) X is the same or different, and glutamate Single base change from coding codon

 Glu

 It is one of at least any one selected from the group consisting of different amino acids, ie, valine, alanine, glycine, lysine, aspartic acid and glutamine.

[0043] (viii) X is the same or different and is a single-base mutation from the codon encoding glutamine

 Gin

 At least one selected from the group consisting of leucine, proline, arginine, lysine, histidine and glutamic acid.

[0044] (ix) X is the same or different, and is a single base change from the codon encoding asparagine.

 Asn

 [0045] (X) X may be the same or different. At least one selected from the group consisting of different amino acids, ie, isoleucine, threonine, serine, tyrosine, histidine, lysine and aspartic acid. Due to a single base mutation from the codon encoding lysine.

 ys

 And at least one selected from the group consisting of isoleucine, methionine, threonine, arginine, glutamine, asparagine, and glutamic acid.

[Xi] X is the same or different and is a single base from the codon encoding aspartic acid. It is at least one selected from the group consisting of amino acids generated by mutation, ie, valine, alanine, glycine, tyrosine, histidine, glutamic acid, and asparagine.

 [0047] (xii) X is the same or different and is a single base change from the codon encoding tryptophan.

 Trpl

 It is at least one selected from the group consisting of different amino acids, namely leucine, serine, arginine, cysteine and dalysin.

[0048] (xiii) X is the same or different and is one from the codons encoding alanine and tryptophan.

 Trp2

 It is at least one selected from the group consisting of amino acids generated by base mutations, that is, leucine, serine, arginine, cystine and glycine, preferably alanine.

 [0049] (xiv) X is the same or different and represents a single-base mutation from the codon encoding alanine.

 Ala

 Thus, the resulting amino acid is at least one selected from the group consisting of valine, aspartic acid, glutamic acid, glycine, serine, proline and threonine.

[0050] (XV) X is the same or different from the codons encoding alanine and phenylalanin.

 Phe

 At least one selected from the group consisting of serine, tyrosine, cysteine, leucine, isoleucine and parin, preferably alanine.

 [0051] Further, the amino acids of B 歹 IJ, C 歹 IJ, F column and G column may be substituted according to the following rule (xvi).

 [0052] (xvi) In Table I;! -6th row, two amino acids in columns B and C in the same row, and two amino acid forces in columns F and G, respectively,

 The same or different acidic amino acids, or

 The same or different basic amino acids,

 Here, in the same fi,

 When the two amino acids in columns B and C are acidic amino acids, the two amino acids in columns F and G are basic amino acids,

When the two amino acids in columns B and C are basic amino acids, the two amino acids in columns F and G are acidic amino acids. [0053] That is, assuming that the acidic amino acid is X and the basicity is X, for example, 7 amino acids in the second row

 A B

 The acid sequences are (A) Χ— Χ —X —Χ— Χ— 順 — in the order 2A-2B-2C-2D-2E-2F-2G

 A A B

 X (SEQ ID NO: 8) or (/ 3) X— X -X -X-X-X -X (SEQ ID NO: 9) (where X is

B B B A A

 (Representing amino acids in columns A, D, and E, respectively). In the present invention, the amino acid sequence IJ located in the 2nd to 4th rows can be obtained by combining the amino acid sequences combined in the order shown in (a) and (β). Moreover, as long as the effects of the present invention are not impaired, (α) and (/ 3) can be arbitrarily combined and used, for example, (<<)-)-)-); 3) — (/ 3

 )-(«)-()-(«)-(Α)-(β) and the like. In the present invention, it is more preferable! /, And the combination is (α)-(α)-(α) — (α); (/ 3) — (/ 3) — (α) — (α ); (α)-(/ 3)-(α)-(/ 3) and the like. It should be noted that 1F -1G and 6B-6C amino acids follow the same rules as X-X or X-X.

 A A B B

 It ’s been modified.

 [0054] Here, the acidic amino acid is preferably glutamic acid, aspartic acid, cystic acid or the like, more preferably glutamic acid or aspartic acid, and still more preferably glutamic acid.

 [0055] The basic amino acid is preferably lysine, arginine, ornithine or histidine, more preferably lysine, arginine or ornithine, more preferably lysine or arginine, and still more preferably. Lysine.

 [0056] Among the combinations of the acidic amino acid and the basic amino acid, the combination of lysine glutamate is more preferable!

 [0057] The amino acids shown in Table I are bound in the following order with R as the N-terminus.

 1

 R -1D-1E-1F-1G-2A-2B-2C-2D-2E-2F-2G-3A-3B-3C-3D-3E-3F-3G-4A-4B-4

1

 C-4D-4E-4F-4G-5A-5B-5C-5D-5E-5F-5G-6A-6B-6C-6D-R

 However, 1D-1E-1F-1G may lack the N-terminal side force. That is, X -X

 Tyr Th

-X -X (SEQ ID NO: 10), X -X -X (SEQ ID NO: 11), X -X, or x r Ser Leu Thr Ser Leu Ser Leu Leu

 It is. Here, the amino acids represented as x -x -x -x (SEQ ID NO: 10) are respectively

 Tyr Thr Ser Leu

 Replaced by the same rules as above!

[0058] The polypeptide of the present invention has the following amino acids (a) to (u) in the amino acid sequence shown in Table I: Those with the amino acid sequence shown are preferred

 [0059] (a) In Table I,

 X

 X is threonine

 Thr

 X is serine,

 X is glutamic acid,

 Glu

 X is glutamine,

 Gin

 X is Asparagine,

 Asn

 X force s lysine,

 ys

 X is aspartic acid,

 Asp

 X and X cationophane,

Trpl Tr _P 2

 X is alanine,

 Ala

 X is phenylenolanine.

 Phe

 [0060] (ii) In Table I,

 X

 X is threonine

 Thr

 X is serine,

 X is glutamic acid,

 Glu

 X is glutamine,

 Gin

 X is Asparagine,

 Asn

 X force s lysine,

 ys

X is aspartic acid, X and X force S tryptophan,

 Trpl Trp2

 X is alanine,

 Ala

 X is phenylenolanine and

 Phe

 X force alanine, glycine, isoleucine, leucine, methionine, threonine

 1

Selected from the group consisting of! /, Representing one amino acid,

R is an acetyleno group and R is NH.

 (U) In Table I,

 X

 X is threaded

 Thr

X is serine,

 X X

 X is glutamic acid,

 Glu

 X is gnoretamine,

 Gin

 X is Asparagine,

 Asn

 X force s lysine,

 Ys

 X is aspartic acid,

 Asp

 X and X force S tryptophan,

 Trpl Trp2

 X is alanine,

 Ala

 X is phenylenolanine and

 Phe

 X is serine, alanine, glycine, isoleucine, leucine, methionine, thread nin and

1

Any force selected from the group consisting of palin, representing one amino acid,

R is an acetylenic group, and R is NH.

In Table I;! ~ 6 rows, two amino acids in columns B and C in the same row, and two amino acid forces in columns F and G, respectively, are acidic amino acids or basic amino acids, here In the same row, when two amino acids in columns B and C are acidic amino acids, two amino acids in columns F and G are basic amino acids, When the two amino acids in columns B and C are basic amino acids, the two amino acids in columns F and G are acidic amino acids.

[0062] [Modified II]

 The present invention also provides the following polypeptide as variant II, which is modified based on the amino acid sequence (SEQ ID NO: 12) of the HR2 region of HIV-2 EHO strain. That is, the variant Π is a polypeptide containing amino acids in the order represented by the following Π (SEQ ID NO: 2).

[0063] [Table 4

 Table II

6 ser Xi p Xphe ―

[0064] In Table II, R and R are defined as follows.

 3 4

[0065] R is an amino acid sequence in the gp41 HR2 region of HIV-2 IjTrp-Gln-Gln-Trp-Glu-Arg-Gln-V

 Three

 It represents at least one selected from the group consisting of d-Arg-Phe (SEQ ID NO: 13), a variant thereof and an acyl group.

 [0066] A variant of the amino acid sequence represented by SEQ ID NO: 13 is X -X -X -X -X -X -X

 Trp uin uln Trp Glu Arg uin

-X -X -X is expressed, and amino acids are substituted according to the following rules of ~ (xv)

Val Arg Phe

 Modified variants. Preferably, the amino acids corresponding to the B and C columns are dartamic acid, and the amino acids corresponding to the F and G columns are lysine. That is, X -Glu-Glu

 Trp

 -X -X -Lys-Lys-X -Glu-Glu (SEQ ID NO: 14)

 Trp Glu Val

 [0067] R Arg (arginine) is a single base mutation from the codon encoding arginine.

 Three

Amino acids produced by leucine, proline, histidine, glutamine, cystine, tryptophan, serine, glycine, isoleucine, methionine, threonine: At least les selected from the group consisting of one or more!

[0068] When R is an acyl group, 1D (D column 1st row), 1E, 1F, 1G represented in Table I above

 Three

 The N-terminal amino group of the amino acid at position 2A is an acyl group such as acetyl group, propionyl group, butyryl group, benzoyl group, benzyloxycarbonyl group, phthalyl group, formyl group, trifanoloacetyl group, benzyl group, etc. May be bonded to each other, preferably a acetyl group, a propionyl group, a butyryl group, a benzoyl group, a phthalinole group, a honoreminore group, or a trifnoreo acetyl group, more preferably a acetyl group.

[0069] R is the amino acid sequence in gp41 of HIV-2 Asp- Phe- Thr- Ser- Trp- Met- Ala- Tyr- lie- Arg

 Four

 (SEQ ID NO: 15), a variant thereof, at least one selected from the group consisting of an amino group and an amino group having a substituent, and one kind.

[0070] A variant of the amino acid sequence represented by SEQ ID NO: 15 is X -X -X -X -X -X -X

 Asp Phe Thr Ser Trp Met Ala

-X -X -X is expressed, and amino acids are substituted according to the following rules (i) to (xv)

Tyr lie Arg

 Modified variants. Preferably, the amino acids corresponding to the B and C columns are dartamic acid, and the amino acids corresponding to the F and G columns are lysine. That is, X -Lys-Lys

 Asp

 -X -Glu-Glu-X -X -Lys-Lys (SEQ ID NO: 16)

 Ser Ala Tyr

 [0071] When R is an amino group or an amino group having a substituent, X at the 6D position represented in Table II above

 Four

 The C-terminal carbonyl group of the C-terminal amino acid of -NH, methylamino group, dimethylamino

Phe 2

 An amino group such as an amino group, an ethylamino group, a jetylamino group, or a benzylamino group may be bonded, preferably -NH, a methylamino group, a dimethylamino group, an ethylamino group, or a jetamino group, more preferably -NH. Join.

In the present invention, it is more preferable that R is a acetyl group and R is —NH.

 3 4 2

[0073] In Table II,

 X is leucine,

 EU

 X is aspartic acid,

 Asp

 X is alanine,

 X is asparagine

X X is a thread

 X is lysine,

 Ys

 X is glutamic acid,

 Glu

 X is glutamine,

 Gin

 X is methionine,

 X

 l yr

 X

 X is serine,

 Ser

 X is phenylenolanine.

 Phe

 [0074] In addition, 1 to 3 amino acids in Table I may be substituted according to the following rules (i) to (xv).

 [0075] (0 X is the same or different and is due to a single base mutation from the codon encoding leucine.

 EU

 And at least one selected from the group consisting of proline, histidine, glutamine, arginine, phenylalanine, isoleucine, methionine, Norin, serine and tryptophan.

 [0076] (ii) X is the same or different and is generated from a single base change from a codon encoding an acid, ie, a group consisting of valine, alanine, glycine, tyrosine, histidine, glutamic acid, and asparagine. At least one power selected, one kind

[0077] (iii) X is the same or different and is due to a single base mutation from the codon encoding alanine.

 Ala

 And at least one selected from the group consisting of valine, aspartic acid, glutamic acid, glycine, serine, proline and threonine.

[0078] (iv) X is the same or different and is a single base change from the codon encoding asparagine.

 Asn

 One amino acid generated by different species, that is, at least one selected from the group consisting of isoleucine, threonine, serine, tyrosine, histidine, lysine and aspartic acid.

^ o

 [0079] (V) X is the same or different and is a single base mutation from the codon encoding isoleucine.

 He

Amino acids produced by threonine, ie threonine, asparagine, lysine, serine, arginine Or at least one selected from the group consisting of phenyralanine, leucine, methionine and parin.

[0080] (vi) X is the same or different and is a single base mutation from a codon encoding threonine

 Thr

 At least one selected from the group consisting of isoleucine, methionine, asparagine, lysine, serine, arginine, proline and alanine.

 [0081] (vii) X is the same or different and ys is due to a single base mutation from the codon encoding lysine.

 And at least one selected from the group consisting of isoleucine, methionine, threonine, arginine, dartamine, asparagine and glutamic acid.

 [0082] (viii) X is the same or different and is a single base change from the codon encoding glutamic acid.

 Glu

 It is one of at least any one selected from the group consisting of different amino acids, ie, valine, alanine, glycine, lysine, aspartic acid and glutamine.

[0083] (ix) X is the same or different and is a single base mutation from the codon encoding glutamine.

 Gin

 Thus, the resulting amino acid is at least one selected from the group consisting of leucine, proline, anoleginine, lysine, histidine and glutamic acid.

[0084] (X) X is the same or different and is a single base mutation from the codon encoding methionine

 Met

 At least one selected from the group consisting of leucine, norin, isoleucine, threonine, lysine and arginine.

 [0085] (xi) X is the same or different and represents a single base mutation from the codon encoding tyrosine.

 Tyr

 Thus, the resulting amino acid, ie, at least one selected from the group consisting of phenylalanine, serine, cystine, histidine, asnoragin and aspartic acid is one.

[0086] (xii) X is the same or different and represents a single base change from the codon encoding tryptophan.

 Trp

 It is at least one selected from the group consisting of different amino acids, namely leucine, serine, arginine, cysteine and dalysin.

[0087] (xiii) X is the same or different and is due to a single base mutation from the codon encoding serine.

 Ser

The resulting amino acids: phenylalanine, leucine, tyrosine, cysteine, tryptophan, proline, thread nin, alanine, isoleucine, wasparagine, anoleginine, glycine At least one force selected from the group consisting of thin and cysteine.

[0088] (xiv) X is the same or different and is a single base from the codon encoding phenylalanin.

 Phe

 And at least one selected from the group consisting of serine, tyrosine, cysteine, leucine, isoleucine and parin.

 [0089] Further, the amino acids of B 歹 IJ, C 歹 IJ, F row and G row may be substituted by the law of (XV). (XV) is defined in the same manner as (xvi) in Table I above.

 [0090] The amino acids shown in Table II are the same as in Table I above, with R as the N-terminus and R as the C-terminus.

 3 4

 Are connected. 1D-1E-1F-1G is defined in the same way as in Table I.

[0091] The amino acid used in the above-mentioned variant I and variant II of the present invention is preferably L-form (Lamino acid), but D-form may also be used. When using D-form, it is preferable to convert all optically active amino acids into D-form.

[0092] The polypeptide of the present invention preferably has any one of the following amino acid sequences (a) to (x). Here, (a) to (v) correspond to variant I, and (w) and (X) correspond to variant II. More preferably, the polypeptide of the present invention has the following amino acid sequences (g) to (n).

 a) Tyr_Tnr_Ser_Leu_Ile_His_Ser_Leu_Ile_Glu_Glu_Ala_Gln_Asn_Gln_Gln_Glu_Lys _Asn_Glu_Gln_Glu_Leu_Leu_Glu_Leu_Asp_Lys_Trp_AlaTrp_L_P

 (b) Tyr_Thr_Ser_Leu_Ile_His_Ser_Leu_Iie_Glu_Glu_Ile_Gin_Asn_Gln_Gin_Glu_Lys _Asn_Glu_Gln_Glu_Leu_Leu_Glu_Leu_Asp_Lys_Trp_AlaTrp_L_P

 c) Tyr_Tnr_Ser_Leu_Ile_His_Ser_Leu_Ile_Glu_Glu_Leu_Gln_Asn_Gln_Gln_Glu_Ly s_Asn_Glu_Gln_Glu_Leu_Leu_Glu_Leu_Asp_Lys_Trp_LlaTrp_L

 d) Tyr_Thr_Ser_Leu_Ile_His_Ser_Leu_Iie_Glu_Glu_Met_Gln_Asn_Gln_Gln_Glu_Ly s_Asn_Glu_Gln_Glu_Leu_Leu_Glu_Leu_Asp_Lys_Trp_AlaTrp_L_P

, E) Tyr_Tnr_Ser_Leu_Ile_His_Ser_Leu_Iie_Glu_Glu_Thr_Gin_Asn_Gln_Gin_Glu_Ly s_Asn_Glu_Gln_Glu_Leu_Leu_Glu_Leu_Asp_Lys_Trp_L_Srp Phe (SEQ ID NO: 21)

 (f) Tyr_Thr_Ser_Leu_Ile_His_Ser_Leu_Ile_Glu_Glu_Val_Gln_Asn_Gln_Gln_Glu_Lys _Asn_Glu_Gln_Glu_L u_L u_Glu_L u_Asp_Lys_Trp_ u_Trp_ u

 (g) Tyr_Thr_Ser_Leu- Ile_Glu_Glu_Leu- Ile_Lys_Lys_Ser_Glu_Glu_Gln_Gln_Lys_Lys _Asn_Glu_Glu_Glu_Leu_Lys_Lys_Leu_Glu_Glu_Trp_AlaTrp_ys

 (h) Tyr_Thr_Ser_Leu_ne_Glu_Glu_Leu_Ile_Lys_Lys_Ala_Glu_Glu_Gln_Gln_Lys_Ly s-Asn-Glu-Glu-Glu-Leu-Lys-Lys-Leu-Glu-Glu-Trp-Ala-Lrp-ys-Trp-Ala-Lrp-ys-T

 (i) Tyr_Thr_Ser_Leu_ne_Glu_Glu_Leu_Ile_Lys_Lys_Gly_Glu_Glu_Gln_Gln_Lys_Lys _Asn_Glu_Glu_Glu_Leu_Lys_Lys_Leu_Glu_Glu_Trp_Ala_Lrp_ys_T__

 (j) Tyr_Thr_Ser_Leu_ne_Glu_Glu_Leu_ne_Lys_Lys_Ile_Glu_Glu_Gln_Gln_Lys_Lys_ Asn_Glu_Glu_Glu_Leu_Lys_Lys_Leu_Glu_Glu_Trp_Ala_Lys_hysTrp_T

 (k) Tyr_Thr_Ser_Leu_Ile_Glu_Glu_Leu_Ile_Lys_Lys_Leu_Glu_Glu_Gln_Gln_Lys_Ly s-Asn-Glu-Glu-Glu-Leu-Lys-Lys-Leu-Glu-Glu-Trp-Lla-Trp-L

 (l) Tyr_Thr_Ser_Leu_ne_Glu_Glu_Leu_Ile_Lys_Lys_Met_Glu_Glu_Gln_Gln_Lys_Ly s-Asn-Glu-Glu-Glu-Leu-Lys-Lys-Leu-Glu-Glu-Trp-Ala-Lrp-ys-Trp-Ala-Lrp-ys

 (m) Tyr_Thr_Ser_Leu_Ile_Glu_Glu_Leu_Ile_Lys_Lys_Thr_Glu_Glu_Gln_Gln_Lys_Ly s-Asn-Glu-Glu-Glu-Leu-Lys-Lys-Leu-Glu-Glu-Trp-Lla-Trp-L

(n) Tyr_Thr_Ser_Leu_ne_Glu_Glu_Leu_Ile_Lys_Lys_Vai_Glu_Glu_Gln_Gln_Lys_Ly s-Asn-Glu-Glu-Glu-Leu-Lys-Lys-Leu-Glu-Glu-Trp-Ala-Lrp-ys-Trp-Ala-Lrp-ys (O) Ile_Glu_Glu_Leu- Ile_Lys_Lys_Ser_Glu_Glu_Gln_Gln_Lys_Lys_Asn_Glu_Glu_Gl u-Leu-Lys-Lys-Leu-Glu-Glu-Trp-Ala-Lys-Lys-Trp-Asn-Trp-Phe (Rooster himself 歹 lj number 31) (p) Tyr_Thr_Ser_Leu_ne_Glu_Glu_Leu_Ile_Lys_Lys_Ser_Glu_Glu_Gln_Gln_Lys_Ly s_Asn_Glu_Glu_Glu_Leu_Lys_Lys_Leu_Glu_Glu_Ala_Ala_Lys_Lys_Trp_Asn_Trp_ Phe ( (SEQ ID NO: 32)

 (q) Tyr_Thr_Ser_Leu_ne_Glu_Glu_Leu_Ile_Lys_Lys_Ser_Glu_Glu_Gln_Gln_Lys_Ly s_Asn_Glu_Glu_Glu_Leu_Lys_Lys_Leu_Glu_Glu_Trp_AlaT

 (r) Tyr_Thr_Ser_Leu- Ile_Glu_Glu_Leu- Ile_Lys_Lys_Ser_Glu_Glu_Gln_Gln_Lys_Lys _Asn_Glu_Glu_Glu_Leu_Lys_Lys_Leu_Glu_Glu_Trp_AlaTrp_ys_Lrp_A

 (s) Tyr_Thr_Ser_Leu- Ile_Lys_Lys_Leu- Ile_Glu_Glu_Ser_Lys_Lys_Gln_Gln_Glu_Glu _Asn_Glu_Glu_Glu_Leu_Lys_Lys_Leu_Glu_Glu_Trp_AlaTrp_ys

 (t) Tyr_Thr_Ser_Leu- Ile_Glu_Glu_Leu- Ile_Lys_Lys_Ser_Lys_Lys_Gln_Gln_Glu_Glu _Asn_Lys_Lys_Glu_Leu_Glu_Glu_Leu_Glu_Glu_Trp_AlaTrp_Lrp_H

 (u) Tyr_Thr_Ser_Leu_ne_Glu_Glu_Leu_Ile_Lys_Lys_Ser_Lys_Lys_Gln_Gln_Glu_Gl u_Asn_Glu_Glu_Glu_Leu_Lys_Lys_Leu_Lys_Lys_Trp_Ala_Trp_lu_he

 (v) Tyr_Thr_Ser_Leu- Ile_Lys_Lys_Leu- Ile_Glu_Glu_Ser_Glu_Glu_Gln_Gln_Lys_Lys _Asn_Glu_Glu_Glu_Leu_Lys_Lys_Leu_Lys_Lys_Trp_AlaTrp_lu_p

 (w) Leu_Asp_Ala_Asn_Ile_Thr_Lys_Leu_Leu_Glu_Glu_Ala_Gln_Ile_Gln_Gln_Glu_L ys_Asn_Met_Tyr_Glu_Leu_Gln_Lys_Leu_Asn_Gln_Trp_hepT

(x) Leu_Asp_Ala_Asn_Ile_Glu_Glu_Leu_Leu_Lys_Lys_Ala_Glu_Glu_Gln_Gln_Lys_L ys_Asn_Glu_Glu_Glu_Leu_Lys_Lys_Leu_Glu_Glu_Trp_Asp_Ler_ys -Phe (SEQ ID NO: 40)

 The polypeptide of the present invention can form a stable α_helix structure when the N-terminus is acetylated and the C-terminus is amidated. In the modified peptide of the present invention, the heel end and the C terminus are not bonded to each other and are preferably acyclic.

[0093] The polypeptide of the present invention can be produced by a known polypeptide synthesis method, particularly a liquid phase synthesis method or a solid phase synthesis method. In addition, it is possible to synthesize DN by encoding the polypeptide of the present invention into a host cell by gene recombination technique and expressing it.

 [0094] For example, in the solid phase synthesis method, N-protected amino acid in which the amino group of the amino acid most corresponding to the C-terminus is protected with a urethane-type protecting group such as 9-fluorenylenomethyloxycarbonyl (Fmoc) group is used. After binding the carboxyl group to an insoluble resin having an amino group, the protecting group of the amino group is removed, the protected amino acid is condensed sequentially in the N-terminal direction, and then the protecting group of the insoluble resin and amino acid is deprotected. The polypeptide of the present invention can be obtained.

 [0095] The insoluble resin having an amino group is not particularly limited, but Fmoc-NH-SA L resin (4_ (2 ', 4'-dimethoxyphenyl-Fmoc-aminoethyl) phenoxy linker resin) is preferable. Preferably, the target can be given directly by cleavage.

 [0096] The protected amino acid used for the synthesis of the polypeptide of the present invention can be obtained by protecting a functional group with a known protecting group by a known method, or by using a commercially available protected amino acid. . As a protecting group, use the power of publicity.

 [0097] In preparing a protected amino acid, for example, a known method such as DIPCDI (diisopropylcarposimide) -HOBt (l_hydroxybenzotriazole) method can be used. This condensation reaction can be carried out in a known solvent, and examples thereof include organic solvents such as dimethylformamide. The reagent for removing the protecting group of the amino group is not limited, and the protecting group such as the Fmoc group can be cleaved by a known reagent such as piperidine / dimethylformamide.

 [0098] The progress of the condensation reaction at each stage of the synthesis can be confirmed by a known method such as a ninhydrin reaction method.

[0099] As described above, a protected polypeptide having a desired amino acid sequence can be obtained. [0100] When Fmoc-NH-SAL resin is used as an insoluble resin, the resin and protecting group can be removed simultaneously by treating with TMSBr (trimethylsilyl bromide), TFA (trifluoroacetic acid), etc. Monkey.

 [0101] The polypeptide of the present invention thus obtained can be obtained by publicly known methods such as extraction, recrystallization, various chromatographies (gel filtration, ion exchange, distribution, adsorption), electrophoresis, countercurrent distribution and the like. It can be isolated and purified by means, and a method using reverse phase high performance liquid chromatography is preferred.

 [0102] The polypeptide of the present invention can prevent HIV from invading (infecting) a host cell (eg, T cell) in a living body, or the infected HIV can proliferate in the host cell and further increase. Can be used to prevent HIV infection, prevent the spread of HIV-infected cells, prevent the development of AIDS, and treat AIDS.

 [0103] 2. Pile HIV agent and pharmaceutical composition containing the pile HIV agent

 The polypeptides of the present invention also include pharmaceutically acceptable salts thereof. Examples of the strength and the salt include non-toxic alkali metal salts such as sodium, potassium, lithium, strength, magnesium, and alkaline earth metal salts prepared by methods well known in the art. Further, the above salts include non-toxic acid addition salts obtained by reacting the polypeptide of the present invention with a suitable organic acid or inorganic acid. Typical acid addition salts include, for example, hydrochloride, hydrobromide, sulfate, acetate, valerate, laurate, lactate, phosphate, p-toluenesulfonate (tosylate), Examples include citrate, maleate, fumarate, succinate, tartrate, glycolate, benzenesulfonate and methanesulfonate. These salts can be used alone or in combination of two or more.

[0104] In addition, the polypeptide of the present invention or a pharmaceutically acceptable salt thereof is each independently an active ingredient, or the polypeptide of the present invention and one or more of its salts are combined as an active ingredient. It can also be used as an anti-HIV agent. In addition, conventionally known additives such as isotonic agents, inorganic salts, buffers, solubilizers, chelating agents, antioxidants, fragrances, preservatives, and pH adjusters may be added to the above polypeptides. V in a range, combining in a range, It can also be used as the anti-HIV agent of the present invention.

 [0105] Furthermore, the present invention comprises the above-mentioned anti-HIV agent as an active ingredient, together with a conventionally known pharmaceutically acceptable carrier or various additives (excipient, diluent, binder, disintegrant, etc.). A pharmaceutical composition having anti-HIV activity is also provided.

 [0106] Various preparation forms of the pharmaceutical composition can be selected depending on the purpose of treatment, and representative examples thereof include tablets, pills, powders, solutions, suspensions, capsules, sustained release. Liquid preparations for oral or parenteral administration, such as solid preparations such as microcapsules and injections (solutions, suspensions, etc.).

 [0107] For example, in the case of forming into a tablet form, the above-mentioned preparation carrier is shaped like lactose, sucrose, sodium chloride, dextrose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, key acid, potassium phosphate, etc. Agent: Water, ethanol, propanol, simple syrup, glucose solution, starch solution, gelatin solution, binder such as carboxymethylcellulose, hydroxypropyl cellulose, methylcellulose, polybutylpyrrolidone; sodium carboxymethylcellulose, carboxymethylcellulose calcium, low substitution degree Disintegrants such as hydroxypropyl pill cellulose, dried starch, sodium alginate, agar powder, laminaran powder, sodium bicarbonate, calcium carbonate; polyoxyethylene sorbitan fatty acid esters, lauric Surfactants such as sodium sulfate and stearic acid monoglycerides; disintegration inhibitors such as sucrose, stearin, cocoa butter and hydrogenated oil; absorption accelerators such as quaternary ammonium base and sodium lauryl sulfate; glycerin and starch Moisturizers; adsorbents such as starch, lactose, kaolin, bentonite, colloidal carboxylic acid; lubricants such as purified tanolate, stearate, boric acid powder, polyethylene glycol, etc. can be used.

 [0108] Further, the tablets can be made into tablets with ordinary coatings as necessary, for example, sugar-coated tablets, gelatin-encapsulated tablets, film-coated tablets, double tablets or multilayer tablets.

 [0109] When forming into a pill form, excipients such as glucose, lactose, starch, cacao butter, hydrogenated vegetable oil, kaolin, talc; gum arabic powder, tragacanth powder, gelatin, ethanol, etc. For example, disintegrants such as laminaran and agar can be used.

[0110] Capsules are prepared according to conventional methods V, and various preparations exemplified above for the active ingredients of the present invention. It is prepared by mixing with a carrier and filling hard gelatin capsules, soft capsules, and the like.

[0111] When the pharmaceutical composition of the present invention is prepared as a liquid preparation for oral administration, a pharmaceutically acceptable solution, emulsion, suspension or syrup containing a conventional inert diluent such as water. , Elixirs and the like, and further auxiliary agents such as wetting agents, emulsions, suspensions and the like can be added, and these are prepared according to a conventional method.

 [0112] When the pharmaceutical composition of the present invention is prepared as a liquid preparation for parenteral administration, diluents such as water, ethyl alcohol, propylene glycol, polyethylene glycol, ethoxyethylene sorbitan fatty acid esters and vegetable oils such as olive oil, etc. And injectable organic esters such as ethyl oleate. Furthermore, usual solubilizers, buffers, wetting agents, emulsifiers, suspending agents, preservatives, dispersing agents and the like can be added to these. Sterilization can be performed by, for example, filtration operation through a bacteria retention filter, blending of a bactericide, irradiation treatment, and heat treatment. They can also be prepared in the form of sterile solid compositions that can be dissolved in sterile water or a suitable sterilizable medium immediately before use.

 [0113] When the pharmaceutical composition of the present invention is prepared in the form of a liquid preparation, it is lyophilized to a state that can be stored, and then dissolved in a buffer solution containing water for use, saline, etc. It can also be used after adjusting to an appropriate concentration.

 [0114] Further, the pharmaceutical composition of the present invention includes various components that can be used in ordinary protein preparations, such as stabilizers, bactericides, buffers, isotonic agents, chelating agents, pH adjusters, A surfactant, phospholipid, and the like can be used as appropriate.

 [0115] It should be noted that the pharmaceutical composition of the present invention may contain a colorant, a preservative, a fragrance, a flavoring agent, a sweetening agent, and other pharmaceuticals as necessary.

[0116] The administration method of the anti-HIV agent or the pharmaceutical composition having anti-HIV activity of the present invention is determined according to various preparation forms, the degree of disease, etc., which are not particularly limited. For example, tablets, pills, liquids, suspensions, emulsions, granules, and capsules are administered orally, and injections are administered alone or mixed intravenously with normal fluids such as glucose or amino acids. If necessary, it can be administered alone intramuscularly, intradermally, subcutaneously or intraperitoneally. [0117] The dosage of the above pharmaceutical composition is not particularly limited, and is appropriately selected depending on the desired therapeutic effect, administration method, treatment period, age of livestock, etc. The effective component amount is about 0.01 g to 10 mg, preferably about 0.1 ^ gl mg, more preferably about 0.01 mg to l mg, more preferably about 0.1 mg to l mg per kg of body weight per day. With good strength, the preparation can be administered once or several times a day. By administering the above-mentioned dose of the active ingredient, HIV infection can be prevented or treated, and in addition, the ability to treat human AIDS can be improved.

 [0118] In addition, in the prevention or treatment of HIV infection or the treatment of human AIDS, the polypeptide of the present invention, the anti-HIV agent or the pharmaceutical composition containing the anti-HIV agent is, for example, currently practiced in the clinical field. It can also be used in combination with other known therapies such as HAART (Highly Active Anti-retroviral Therapy).

 Example

 Hereinafter, the ability to explain the present invention in more detail using examples The present invention is not limited to these examples.

 (1) Peptide synthesis

 On NovaSyn TGR resin (Novabiochem), a protective peptide resin was constructed by the usual Fmoc type solid phase synthesis method. At the N-terminus, acetylation was performed by adding acetic anhydride (10 eq.) And pyridine (10 eq.) And stirring in DMF solvent for 2 hr. This resin (200 mg) was treated with m-cresol: eth anedithiol: thioanisole: H 2 O: TFA = 5: 5: 5: 5: 80 (v / v, 10 mL) at room temperature for 2.5 hr. After removing the resin by filtration, the solvent was distilled off with a nitrogen stream, and ether was added to the residue under ice cooling to precipitate the peptide. The peptide was precipitated with a centrifuge to remove ether, and this washing operation was repeated three times. The crude peptide was dissolved in 0.1% TFA in H 2 O-MeCN (1: 2 v / v, 5 mL), and fractionated and purified by HPLC to obtain the desired peptides (a) to (x). The results of mass spectrometry obtained by ion spray mass spectrometry (using IS-MSX triple stage quadrupole mass spectrometer 装置 (Perkin-Elmer ScieX)) under each amino acid sequence are shown.

[0120] (a) T20 / S138A

Tyr_Thr_Ser_Leu_Ile_His_Ser_Leu_Ile_Glu_Glu_Ala_Gln_Asn_Gln_Gln_Glu_Lys_A sn_Glu_Gln_Glu_Leu_Leu_Glu_Leu_Asp_Lys_Trp_Ala_Ser_Leu_Trp_Asn_Trp_Phe (SEQ ID NO: 17)

 (Theoretical value: 4476.9; Actual value: 4476.0)

 (b) T20 / S138I

 Tyr_Thr_Ser_Leu_Ile_His_Ser_Leu_Ile_Glu_Glu_Ile_Gin_Asn_Gln_Gin_Glu_Lys_A sn-Glu-Gln-Glu-Leu-Leu-Glu-Leu-Asp-Lys-Trp-Ala-T-P

 (Theoretical value: 4519.0; Actual value: 4518.4)

 (c) T20 / S138L

 Tyr_Thr_Ser_Leu_Ile_His_Ser_Leu_Ile_Glu_Glu_Leu_Gln_Asn_Gin_Gln_Glu_Lys_ Asn_Glu_Gln_Glu_Leu_Leu_Glu_Leu_Asp_Lys_Trp_Ala_Ser_Leu_rp

 (Theoretical value: 4519.0; Actual value: 4518.7)

 (d) T20 / S138M

 Tyr_Thr_Ser_Leu_Ile_His_Ser_Leu_Ile_Glu_Glu_Met_Gln_Asn_Gln_Gln_Glu_Lys_ Asn_Glu_Gln_Glu_Leu_Leu_Glu_Leu_Asp_Lys_Trp_Ala_Ser_Leu_T__

 (Theoretical value: 4537.0; Actual value: 4536.1)

 (e) T20 / S138T

 Tyr_Thr_Ser_Leu_Ile_His_Ser_Leu_Ile_Glu_Glu_Thr_Gln_Asn_Gln_Gln_Glu_Lys_ Asn_Glu_Gln_Glu_Leu_Leu_Glu_Leu_Asp_Lys_Trp_Ala_Ser_Leu_T

 (Theoretical value: 4506.9; Actual value: 4506.4)

 (i) T20 / S138V

 Tyr_Thr_Ser_Leu_Ile_His_Ser_Leu_Ile_Glu_Glu_Val_Gln_Asn_Gln_Gln_Glu_Lys_A sn-Glu-Gln-Glu-Leu-Leu-Glu-Leu-Asp-Lys-Trp-Ala-Ser-Ln-rp-T-P

(Theoretical value: 4504.9; Actual value: 4504.8) (g) T20E

 Tyr_Thr_Ser_Leu_Ile_Glu_Glu_Leu_Ile_Lys_Lys_Ser_Glu_Glu_Gln_Gln_Lys_Lys_ Asn_Glu_Glu_Glu_Leu_Lys_Lys_Leu_Glu_Glu_Trp_Ala_Lys_hys

 (Theoretical value: 4626.2; Actual value: 4625.5)

 (h) T20E / S138A

 Tyr_Thr_Ser_Leu_Ile_Glu_Glu_Leu_Ile_Lys_Lys_Ala_Glu_Glu_Gln_Gin_Lys_Lys_ Asn_Glu_Glu_Glu_Leu_Lys_Lys_Leu_Glu_Glu_Trp_Ala_Lys_P

 (Theoretical value: 4610.2; Actual value: 4610.0)

 (i) T20E / S138G

 Tyr_Thr_Ser_Leu_Ile_Glu_Glu_Leu_Ile_Lys_Lys_Gly_Glu_Glu_Gln_Gln_Lys_Lys_ Asn_Glu_Glu_Glu_Leu_Lys_Lys_Leu_Glu_Glu_Trp_Ala_Lys_P

 (Theoretical value: 4696.2; Actual value: 4696.0)

 (j) T20E / S138I

 Tyr_Thr_Ser_Leu_Ile_Glu_Glu_Leu_Ile_Lys_Lys_Ile_Glu_Glu_Gin_Gln_Lys_Lys_A sn_Giu_Giu_Glu_Leu_Lys_Lys_Leu_Giu_Giu_Trp_Ala_Lys_Lys_rp_T

 (Theoretical value: 4652.3; Actual value: 4652.0)

 (k) T20E / S138L

 Tyr_Thr_Ser_Leu_Ile_Glu_Glu_Leu_Ile_Lys_Lys_Leu_Glu_Giu_Gln_Gln_Lys_Lys_ Asn_Glu_Glu_Glu_Leu_Lys_Lys_Leu_Glu_Glu_Trp_Ala_Lys_Lys_rp_T

 (Theoretical value: 4652.3; Actual value: 4652.0)

 (1) T20E / S138M

Tyr_Thr_Ser_Leu_Ile_Glu_Glu_Leu_Ile_Lys_Lys_Met_Glu_Glu_Gln_Gln_Lys_Lys_ Asn_Glu_Glu_Glu_Leu_Lys_Lys_Leu_Glu_Glu_Trp_Ala_Lys_Lys_rp e (SEQ ID NO: 28)

 (Theoretical value: 4670.3; Actual value: 4669.2)

 (m) T20E / S138T

 Tyr_Thr_Ser_Leu_Ile_Glu_Glu_Leu_Ile_Lys_Lys_Tnr_Glu_Glu_Gln_Gln_Lys_Lys_ Asn_Glu_Glu_Glu_Leu_Lys_Lys_Leu_Glu_Glu_Trp_Ala_Lys_hysTrp_Ala_Lys_hys

 (Theoretical value: 4640.2; Actual value: 4640.0)

 (n) T20E / S138V

 Tyr_Thr_Ser_Leu_Ile_Glu_Glu_Leu_Ile_Lys_Lys_Va 卜 Glu_Glu_Gln_Gin_Lys_Lys_ Asn_Glu_Glu_Glu_Leu_Lys_Lys_Leu_Glu_Glu_Trp_Ala_Lys_P

 (Theoretical value: 4638.2; Actual value: 4638.0)

 (o) T20E 32

 Ile-Glu-Glu-Leu-Ile-Lys-Lys-Ser-Glu-Glu-Gln-Gln-Lys-Lys-Asn-Glu-Glu-Glu- Leu-Lys-Lys-Leu-Glu-Glu-Trp- Ala-Lys-Lys-Trp-Asn-Trp-Phe (SEQ ID NO: 31) (theoretical value: 4161.7; actual value: 4162.0)

(p) T20E / W155A

 Tyr_Thr_Ser_Leu_Ile_Glu_Glu_Leu_Ile_Lys_Lys_Ser_Glu_Glu_Gln_Gin_Lys_Lys_ Asn_Glu_Glu_Glu_Leu_Lys_Lys_Leu_Glu_Glu_Ala_Ala_Lys_Lys_rp_T

 (Theoretical value: 4511.1; Actual value: 4511.2)

 (q) T20E / W161A

 Tyr_Thr_Ser_Leu_Ile_Glu_Glu_Leu_Ile_Lys_Lys_Ser_Glu_Glu_Gln_Gin_Lys_Lys_ Asn_Glu_Glu_Glu_Leu_Lys_Lys_Leu_Glu_Glu_Trp_Ala_Lys_Lys_rp

 (Theoretical value: 4511.1; Actual value: 4511.0)

 (r) T20E / F162A

Tvr_Thr_Ser_Leu_Ile_Glu_Glu_Leu_Ile_Lys_Lys_Ser_Glu_Glu_Gln_Gin_Lvs_Lys_ Asn_Glu_Glu_Glu_Leu_Lys_Lys_Leu_Glu_Glu_Trp_Ala_Lys_Lys_Trp_Asn_Trp_Al a (SEQ ID NO: 34)

 (Theoretical value: 4550.1; Actual value: 4550.0)

 (s) T20E -b

 Tyr_Thr_Ser_Leu_Ile_Lys_Lys_Leu_Ile_Glu_Giu_Ser_Lys_Lys_Gln_Gln_Glu_Glu_ Asn_Glu_Glu_Glu_Leu_Lys_Lys_Leu_Glu_Glu_Trp_Ala_Lys_P

 (Theoretical value: 4626.2; Actual value: 4626.0)

 (t) T20E -d

 Tyr_Thr_Ser_Leu_Ile_Glu_Glu_Leu_Ile_Lys_Lys_Ser_Lys_Lys_Gln_Gln_Glu_Glu_ Asn_Lys_Lys_Glu_Leu_Glu_Glu_Leu_Glu_Glu_Trp_Ala_Lys_Lys_rp_T

 (Theoretical value: 4626.2; Actual value: 4626.0)

 (u) T20EK-g

 Tyr_Thr_Ser_Leu_Ile_Glu_Glu_Leu_Ile_Lys_Lys_Ser_Lys_Lys_Gln_Gln_Glu_Glu_ Asn_Glu_Glu_Glu_Leu_Lys_Lys_Leu_Lys_Lys_Trp_Ala_Glu_hlurp

 (Theoretical value: 4626.2; Actual value: 4626.0)

(V) T20E -h

 Tyr_Thr_Ser_Leu_Ile_Lys_Lys_Leu_Ile_Glu_Giu_Ser_Glu_Glu_Gln_Gin_Lys_Lys_ Asn_Glu_Glu_Glu_Leu_Lys_Lys_Leu_Lys_Lys_Trp_Ala_Glu_hlurp

 (Theoretical value: 4626.2; Actual value: 4626.0)

 (w) T20 / HIV-2

 Leu_Asp_A _Asn_Ile_Thr_Lys_Leu_Leu_Glu_Glu_Ala_Gin_Ile_Gln_Gln_Giu_Lys_ Asn_Met_Tyr_Giu_Leu_Lrln_Lys_Leu_Asn_Lrln_l rp_Ap_ Irp_hep n

(Theoretical value: 4485.0; Actual value: 4485.0) (x) T20E / HIV-2

 Leu_Asp_Ala_Asn_Ile_Glu_Glu_Leu_Leu_Lys_Lys_Ala_Glu_Glu_Gln_Gln_Lys_Lys _Asn_Glu_Glu_Glu_Leu_Lys_Lys_Leu_Glu_Glu_Trp_Asp_Lys_Lys_P

 (Theoretical value: 4504.0; Actual value: 4503.5)

[0121] (2) Measurement of anti-HIV activity by MAGI (Maltinuclear activation of galactosidase indicator)

 Using MAGI cells in which CD4-LTR / βgal was expressed in Hela cells, anti-HIV activity was measured for the polypeptides comprising the sequences (a) to (o) described above by MAGI assay.

[0122] After treating MAGI cells with trypsin for 5 minutes, an equal amount or more of DMEM (Dulbecco's Modified Eagle's Medium) was added, and after counting, 96 wells were adjusted to 1 X 10 ⁴ cells / well. Viral HIV-clone clone NL4-3 was diluted with DMEM and added to the wells in increments of 100. Polypeptides containing the sequences (a) to (0) above were serially diluted 10-fold and added to the well. After culturing for 48 hours, X-Gal was added and the number of cells stained blue was counted. Since this cell is stained blue with X-GAL when HIV is infected, the concentration that gives a staining rate of 50% is expressed as EC (Effective concentration). The results are shown in Tables A to D below.

[0123] [Table A]

 Table A

[0124] [Table B] Table B

[0125] [Table C]

 Table C

[0126] [Table

From the results shown in Tables A to D, it was shown that the polypeptide of the present invention has an anti-HIV activity superior to that of T20. [0128] (3) Anti-HIV activity against T20 resistant virus

 Anti-HIV activity against T20 resistant virus was evaluated using T20 and the polypeptides (a) to (d) and (g) to (n).

 [0129] Anti-HIV activity was evaluated by the same test method as in (2) above, except that the T20 resistant strain virus was used instead of the virus HIV-red clone NL4-3.

 [0130] In clinical strains exhibiting T20 resistance, mutations such as gp41 V38A and N43D are observed. However, since these T20 resistant viruses have poor growth ability, they were prepared as viruses that can be applied to Atsei by introducing mutations in some sequences (substitution of aspartate at position 36 with glycine). Is described as DG). That is, in this study, the activity value against DG was defined as the activity value against wild type HIV, and the tendency of anti-HIV activity was evaluated using DG / V38A and DG / N43D as viruses corresponding to the mutant strain (T20 resistant strain). Here, DG / V38A is a resistant strain in which palin at position 38 in the HR1 region of gp41 of T20 resistant HIV is mutated to alanine. DG / N43D is a resistant strain in which asparagine at position 43 in the HR1 region of gp41 of T20 resistant HIV is mutated to aspartic acid.

 [0131] As described above, resistance to T20 is thought to be caused by amino acid mutations in the HR1 region and HR2 region of gp41. Here, it is considered that an amino acid mutation in the HR1 region decreases the affinity for T20 having an inhibitory activity as a partial peptide in the HR2 region. On the other hand, amino acid mutations in the HR2 region are thought to retain higher affinity due to the sequence of the HR1 region after the mutation, which has higher affinity than T20. Therefore, in this study, T20-resistant strains having mutations at positions corresponding to the HR1 region of DG gp41 (ie, palin at position 38 and asparagine at position 43) were used, and the peptides of the present invention against these were used. Anti-HIV activity was assessed.

 [0132] The results are shown in Tables E and F below.

[0133] [Table E] Table E

[0134] [Table F]

 Table F

[0135] As shown in Table E and Table F, the polypeptide of the present invention also showed excellent antiviral activity against T20 resistant strains of HIV.

[0136] ⁽⁴⁾ HIV_ anti-HIV activity against ² virus

 Anti-HIV activity against HIV-2 virus was evaluated using T20 and the polypeptides (g), (w) and (X).

 [0137] Anti-HIV activity was evaluated by the same test method as in (2) above, except that HIV-2 EHO strain virus was used instead of virus HIV-red clone NL4-3. The results are shown in Table G below.

[0138] [Table G] Table G

[0139] As shown in Table G, the polypeptide of the present invention showed excellent antiviral activity against HIV-2 (EHO). In particular, the polypeptides (g) and (w) exhibited excellent antiviral activity against HIV-1 and also exhibited excellent antiviral activity against HIV-2.

 Sequence listing free text

[0140] SEQ ID NO: 1 represents the amino acid sequence shown in Table I.

 SEQ ID NO: 2 represents the amino acid sequence shown in Table II.

 SEQ ID NO: 5 represents the amino acid sequence of a variant of HIV-1 (NL4-3) gp41 HR2 region 117-126.

 SEQ ID NO: 7 represents the amino acid sequence of a variant of HIV-1 (NL4-3) gp41 HR2 region 163-173.

 SEQ ID NO: 8 represents the amino acid sequence of (α).

 SEQ ID NO: 9 represents the amino acid sequence of (β).

 SEQ ID NO: 10 represents the amino acid sequence of 1D-1E-1F-1G in Table I

 SEQ ID NO: 11 represents the amino acid sequence of 1E-1F-1G in Table I

 SEQ ID NO: 14 represents the amino acid sequence of a variant of the partial sequence of HIV-2 (EHO) gp41 HR2 region. SEQ ID NO: 16 represents the amino acid sequence of a variant of the partial sequence of HIV-2 (EHO) gp41.

 SEQ ID NO: 17 represents the amino acid sequence of (a) T20 / S138A.

 SEQ ID NO: 18 represents the amino acid sequence of (b) T20 / S138I.

 SEQ ID NO: 19 represents the amino acid sequence of (c) T20 / S138L.

 SEQ ID NO: 20 represents the amino acid sequence of (d) T20 / S138M.

SEQ ID NO: 21 represents the amino acid sequence of (e) T20 / S138T. SEQ ID NO: 22 represents the amino acid sequence of (f) T20 / S138V. SEQ ID NO: 23 represents the amino acid sequence of (g) T20EK.

SEQ ID NO: 24 represents the amino acid sequence of (h) T20EK / S138A. SEQ ID NO: 25 represents the amino acid sequence of (i) T20EK / S138G. SEQ ID NO: 26 represents the amino acid sequence of (j) T20EK / S138I. SEQ ID NO: 27 represents the amino acid sequence of (k) T20EK / S138L. SEQ ID NO: 28 represents the amino acid sequence of (DT20EK / S138M. SEQ ID NO: 29 represents the amino acid sequence of (m) T20EK / S138T. SEQ ID NO: 30 represents the amino acid sequence of (n) T20EK / S138V. No. 31 represents the amino acid sequence of (o) T20EK32 SEQ ID NO: 32 represents the amino acid sequence of (p) T20EK / W155A SEQ ID NO: 33 represents the amino acid sequence of (q) T20EK / W161A SEQ ID NO: 34 (R) represents the amino acid sequence of T20EK / F162A SEQ ID NO: 35 represents the amino acid sequence of (s) T20EK-b.

SEQ ID NO: 36 represents the amino acid sequence of (t) T20EK-d.

SEQ ID NO: 37 represents the amino acid sequence of (u) T20EK-g. SEQ ID NO: 38 represents the amino acid sequence of (v) T20EK-h. SEQ ID NO: 39 represents the amino acid sequence of (w) T20 / HIV_2. SEQ ID NO: 40 represents the amino acid sequence of (x) T20EK / HIV-2.

Claims

The scope of the claims

 Polypeptide containing amino acids in the order shown in Table I below (SEQ ID NO: 1)

[table 1]

 Table I

R

(In Table I, x represents serine, alanine, glycine, isoleucine, leucine, methionine, threo.

 1

Any force selected from the group consisting of nin and valine, representing one amino acid;

 R is an amino acid sequence represented by SEQ ID NO: 4, lj, a variant thereof and a group consisting of an acyl group

1

Represents V selected, one of them;

 R represents at least one selected from the group consisting of the amino acid sequence represented by SEQ ID NO: 6, a variant thereof, an amino group and an amino group having a substituent;

 X is tyrosine,

 Tyr

 X is Thread Nin,

 Thr

 X is serine,

 Ser

 X is leucine,

 EU

 X is isoleucine,

 lie

 X is histidine,

 His

 X is glutamic acid,

 Glu

 X is glutamine,

 Gin

 X is asparagine,

 Asn

 X is lysine,

 ys

X is aspartic acid, X and X are tryptophan,

 Trpl Trp2

 X is alanine,

 Ala

 X is phenylenolanine;

 Phe

 In addition, 1 to 3 amino acids in Table I may be substituted according to the following rules (i) to (xv).

 (0 X is the same or different and is due to a single base mutation from the codon encoding tyrosine.

Tyr

At least one selected from the group consisting of the resulting amino acids, one species;

 (ii) X is the same or different and represents a single base mutation from the codon encoding threonine.

Thr

Thus at least one force selected from the group consisting of the resulting amino acids, one species;

 (iii) X is the same or different and is due to a single base mutation from the codon encoding serine.

Ser

At least one force selected from the group consisting of the amino acids generated by

 (iv) X is the same or different, and eu is due to a single base mutation from the codon encoding leucine.

At least one selected from the group consisting of the resulting amino acids, one species;

 (V) X is the same or different and a single base mutation from the codon encoding isoleucine

He

At least one force selected from the group consisting of amino acids generated by

 (vi) X is the same or different and is a single base mutation from the codon encoding histidine.

His

Thus at least one force selected from the group consisting of the resulting amino acids, one species;

 (vii) X is the same or different and is a single base change from the codon encoding glutamate.

Glu

At least one force selected from the group consisting of different amino acids, one species;

 (viii) X is the same or different, and a single base mutation from the codon encoding glutamine

Gin

At least one force selected from the group consisting of amino acids generated by

 (ix) X is the same or different and is a single base change from the codon encoding asparagine.

Asn

At least one force selected from the group consisting of different amino acids, one species;

 (X) X is the same or different and is a single base mutation from the codon encoding lysine.

At least one force selected from the group consisting of the amino acids generated by

 (xi) X is the same or different and is a single base from the codon encoding aspartic acid.

Asp

At least one force selected from the group consisting of amino acids generated by mutation, one species;

 (xii) X is the same or different and is a single base change from the codon encoding tryptophan.

Trpl At least one force selected from the group consisting of different amino acids, one species;

 (xiii) X is the same or different and is a single base change from the codon encoding tryptophan.

Trp2

At least one selected from the group consisting of amino acids and alanine which are caused by different;

 (xiv) X is the same or different and represents a single base mutation from the codon encoding alanine.

Ala

Thus at least one force selected from the group consisting of the resulting amino acids, one species;

 (XV) X is the same or different, one base from the codon encoding phenylalanin

Phe

And at least one selected from the group consisting of amino acids and alanine produced by mutation of

 Furthermore, the amino acids of B 歹 IJ, C 歹 IJ, F column and G column may be substituted according to the following rule (xvi).

 (xvi) in Table I;! -6 rows, 2 amino acids in columns B and C in the same row, and 2 amino acid forces in columns F and G, respectively,

 Is at least one acidic amino acid selected from the group consisting of glutamic acid, aspartic acid, and cysteic acid.

 It is the same or different and is at least one force selected from the group consisting of lysine, arginine, ornithine and histidine, and one basic amino acid.

 Here, in the same row, when the two amino acids in columns B and C are acidic amino acids, the two amino acids in columns F and G are basic amino acids,

 When the two amino acids in columns B and C are basic amino acids, the two amino acids in columns F and G are acidic amino acids;

 In addition, the amino acids shown in Table I are bound in the following order with R as the N-terminus.

 1

 R -1D-1E-1F-1G-2A-2B-2C-2D-2E-2F-2G-3A-3B-3C-3D-3E-3F-3G-4A-4B-4

1

 C-4D-4E-4F-4G-5A-5B-5C-5D-5E-5F-5G-6A-6B-6C-6D-R

 However, 1D-1E-1F-1G is missing from the N-terminal side in order! /, May! / ヽ;

 Also, if no amino acid other than X is substituted, X is not serine).

 1 1

In Table I above X is serine,

 Ser

 X is leucine,

 EU

 X is isoleucine,

 lie

 X cahistidine,

 His

 X is glutamic acid,

 Glu

 X is gnoretamine,

 Gin

 X is Asparagine,

 Asn

 X force s lysine,

 Ys

 X is aspartic acid,

 Asp

 X and X force S tryptophan,

 Trpl Trp2

 X is alanine,

 Ala

 2. The polypeptide of claim 1, wherein X is phenylalanin.

 Phe

 In Table I above, X force alanine, glycine, isoleucine, leucine, methionine,

 1

The polypeptide according to claim 1 or 2, which is either leonin or parin.

 In Table I, amino acids in columns B and C are glutamic acid, amino acids in columns F and G are lysine,

 And X is alanine, glycine, isoleucine, leucine, methionine, threonine or

 1

One of the phosphorus,

 The polypeptide according to any one of claims 1 to 3, wherein is a acetyl group, R-NH.

Yes

 A polypeptide containing amino acids in the order shown in Table II below (SEQ ID NO: 2).

[Table 2] Table π

(In Table II, R represents an amino acid sequence IJ represented by SEQ ID NO: 13, a modified form thereof, and an acyl group.

 Three

V represents one selected from the group consisting of:

 R has the amino acid sequence represented by SEQ ID NO: 15, a variant thereof, an amino group, and a substituent.

Four

Represents at least one force selected from the group consisting of amino groups;

 X is leucine,

 EU

 X is aspartic acid,

 Asp

 X is alanine,

 Ala

 X is asparagine,

 Asn

 X is isoleucine,

 lie

 X is threonine,

 Thr

 X is lysine,

 Ys

 X is glutamic acid,

 Glu

 X is glutamine,

 Gin

 X is methionine,

 Met

 X is tyrosine,

 Tyr

 X is tryptophan,

 Trp

 X is serine,

 Ser

 X is phenylenolanine;

 Phe

In addition, 1 to 3 amino acids in Table II may be substituted according to the following rules (i) to (xiv). (i) X is the same or different, and eu is caused by a single base mutation from the codon encoding leucine.

At least one selected from the group consisting of the resulting amino acids, one species;

 (ii) X is the same or different and is a single base change from the codon encoding aspartic acid.

Asp

At least one force selected from the group consisting of different amino acids, one species;

 (iii) X is the same or different and is due to a single base mutation from the codon encoding alanine.

Ala

At least one selected from the group consisting of the resulting amino acids, one species;

 (iv) X is the same or different and is a single base change from the codon encoding asparagine.

Asn

At least one force selected from the group consisting of different amino acids, one species;

 (V) X is the same or different and a single base mutation from the codon encoding isoleucine

He

At least one force selected from the group consisting of amino acids generated by

 (vi) X is the same or different and is a single base mutation from the codon encoding threonine.

Thr

At least one force selected from the group consisting of amino acids generated by

 (vii) X is the same or different and is expressed by a single base mutation from the codon encoding lysine.

At least one selected from the group consisting of the resulting amino acids, one species;

 (viii) X is the same or different and is a single base from the codon encoding glutamic acid.

Glu

At least one force selected from the group consisting of amino acids generated by mutation, one species;

 (ix) X is the same or different and is a single base mutation from the codon encoding glutamine.

Gin

Thus at least one force selected from the group consisting of the resulting amino acids, one species;

 (X) X is the same or different and is a single base mutation from the codon encoding methionine

Met

At least one force selected from the group consisting of amino acids generated by

 (xi) X is the same or different and is a single base mutation from the codon encoding tyrosine.

Tyr

Thus at least one force selected from the group consisting of the resulting amino acids, one species;

 (xii) X is the same or different and is a single base change from the codon encoding tryptophan.

Trp

At least one force selected from the group consisting of different amino acids, one species;

 (xiii) X is the same or different and is due to a single base mutation from the codon encoding serine.

Ser

At least one selected from the group consisting of the resulting amino acids, one species;

 (xiv) X is the same or different and is a single base from the codon encoding phenylalanin.

Phe

At least one selected from the group consisting of amino acids generated by mutation of Furthermore, the amino acids of B 歹 IJ, C 歹 IJ, F column and G column may be substituted according to the following rule (xv).

 (xv) in Table II;! ~ 6 rows, two amino acids in columns B and C in the same row, and two amino acid forces in columns F and G, respectively,

 Is at least one acidic amino acid selected from the group consisting of glutamic acid, aspartic acid, and cysteic acid.

 It is the same or different and is at least one force selected from the group consisting of lysine, arginine, ornithine and histidine, and one basic amino acid.

 Here, in the same row, when the two amino acids in columns B and C are acidic amino acids, the two amino acids in columns F and G are basic amino acids,

 When the two amino acids in columns B and C are basic amino acids, the two amino acids in columns F and G are acidic amino acids;

 The amino acids shown in Table II are bound in the following order, with R as the N-terminus.

 Three

 R -1D-1E-1F-1G-2A-2B-2C-2D-2E-2F-2G-3A-3B-3C-3D-3E-3F-3G-4A-4B-4

Three

 C-4D-4E-4F-4G-5A-5B-5C-5D-5E-5F-5G-6A-6B-6C-6D-R

 Four

 However, 1D-1E-1F-1G is missing in order from the N-terminal side! /, May! /)).

 In Table II above

 X is leucine,

 EU

 X is aspartic acid,

 Asp

 X is alanine,

 Ala

 X is asparagine,

 Asn

 X is isoleucine,

 lie

 X is threonine,

 Thr

 X is lysine,

 Ys

 X is glutamic acid,

 Glu

 X is glutamine,

 Gin

X is methionine, X is tyrosine,

 Tyr

 X is tryptophan,

 Trp

 X is serine,

 Ser

 6. The polypeptide according to claim 5, wherein X is phenylenolanine.

 Phe

 In Table II, the amino acids in columns B and C are glutamic acid, the amino acids in columns F and G are lysine,

 The polypeptide according to claim 5 or 6, wherein R is a acetyl group and R is -NH.

 3 4 2

 The polypeptide according to any one of claims 1 to 4, which has any one of the following amino acid sequences (a) to (f):

 (a Tyr_Thr_Ser_Leu_Ile_His_Ser_Leu_Ile_Glu_Glu_Ala_Gin_Asn_Gln_Gin_Glu_Lys _Asn_Glu_Gln_Glu_L u_L u_Glu_L u_Asp_Lys_Trp_ u_Trp_ u

 (WTyr_Thr_Ser_Leu_ne_His_Ser_Leu_Ile_Glu_Glu_Ile_Gln_Asn_Gln_Gln_Glu_Lys _Asn_Glu_Gln_Glu_L u_L u_Glu_L u_Asp_Lys_Trp_Ala ~ S r_n_T_rp_T_rp_T

 (c) Tyr_Thr_Ser_Leu_ne_His_Ser_Leu_Ile_Glu_Glu_Leu_Gln_Asn_Gln_Gln_Glu_Ly s_Asn_Glu_Gln_Giu_L u_L u_Glu_L u_Asp_Lys_Trp_ u_Trp_u

 (d) Tyr_Thr_Ser_Leu_ne_His_Ser_Leu_Ile_Glu_Glu_Met_Gln_Asn_Gln_Gln_Glu_Ly s_Asn_Glu_Gln_Giu_L u_L u_Glu_L u_Asp_Lys_Trp_ u_Trp_ u

 (e) Tyr_Thr_Ser_Leu_Ile_His_Ser_Leu_Ile_Glu_Glu_Thr_Gln_Asn_Gln_Gln_Glu_Ly s_Asn_Glu_Gln_Glu_L u_L u_Glu_L u_Asp_Lys_Trp_Lla_P

 (f) Tyr_Thr_Ser_Leu_Ile_His_Ser_Leu_Ile_Glu_Glu_Val_Gln_Asn_Gln_Gln_Glu_Lys _Asn_Glu_Gln_Glu_L u_L u_Glu_L u_Asp_Lys_Trp_ u_Trp_ u

The po according to any one of claims 1 to 4, which has an amino acid sequence of any of the following (g) to (v): Repeptide.

 (g) Tyr_Thr_Ser_Leu- Ile_Glu_Glu_Leu- Ile_Lys_Lys_Ser_Glu_Glu_Gln_Gln_Lys_Lys _Asn_Glu_Glu_Glu_Leu_Lys_Lys_Leu_Glu_Glu_Trp_AlaTrp_ys

 (h) Tyr_Thr_Ser_Leu_ne_Glu_Glu_Leu_Ile_Lys_Lys_Ala_Glu_Giu_Gln_Gln_Lys_Ly s-Asn-Glu-Glu-Glu-Leu-Lys-Lys-Leu-Glu-Glu-Trp-Ala-Lrp-ys-Trp-Ala-Lrp-ys

 (i) Tyr_Thr_Ser_Leu_ne_Glu_Glu_Leu_Ile_Lys_Lys_Gly_Glu_Glu_Gln_Gln_Lys_Lys _Asn_Glu_Glu_Glu_Leu_Lys_Lys_Leu_Glu_Glu_Trp_Ala_Lrp_ys_T__

 (J) Tyr_Thr_Ser_Leu_ne_Glu_Glu_Leu_ne_Lys_Lys_Ile_Glu_Glu_Gln_Gln_Lys_Lys_ Asn_Glu_Glu_Glu_Leu_Lys_Lys_Leu_Glu_Glu_Trp_Ala_Lys_Lys_Trp_Asn_Trp_Ph e (SEQ ID NO: 26) (k) Tyr- Thr- Ser- Leu- lie- Glu- Glu- Leu- lie- Lys- Lys- Leu- Glu- Glu- Gln_Gln_Lys_Lys_Asn_Glu_Glu_Glu_Leu_Lys_Lys_Leu_Glu_Glu_Trp_Ala_Lys_Ly s-Trp-Asn-Trp -Phe (SEQ ID NO: 27)

 (l) Tyr_Thr_Ser_Leu_ne_Glu_Glu_Leu_Ile_Lys_Lys_Met_Glu_Glu_Gln_Gln_Lys_Ly s-Asn-Glu-Glu-Glu-Leu-Lys-Lys-Leu-Glu-Glu-Trp-Ala-Lrp-ys-Trp-Ala-Lrp-ys

 (m) Tyr_Thr_Ser_Leu_Ile_Glu_Glu_Leu_Ile_Lys_Lys_Thr_Glu_Glu_Gln_Gln_Lys_Ly s-Asn-Glu-Glu-Glu-Leu-Lys-Lys-Leu-Glu-Glu-Trp-Lla-Trp-L

 (n) Tyr_Thr_Ser_Leu_ne_Glu_Glu_Leu_Ile_Lys_Lys_Vai_Glu_Glu_Gln_Gln_Lys_Ly s-Asn-Glu-Glu-Glu-Leu-Lys-Lys-Leu-Glu-Glu-Trp-Ala-Lrp-ys-Trp-Ala-Lrp-ys

(O) Ile_Glu_Glu_Leu- Ile_Lys_Lys_Ser_Glu_Glu_Gln_Gln_Lys_Lys_Asn_Glu_Glu_Gl u- Leu- Lys- Lys- Leu- Glu- Glu- Trp- Ala- Lys- Lys- Trp- Asn- Trp- Phe (Rooster himself 歹 lj number 31) (p) Tyr_Thr_Ser_Leu_ne_Glu_Glu_Leu_Ile_Lys_Lys_Ser_Glu_Glu_Gln_Gln_Lys_Ly s_Asn_Glu_Glu_Glu_Leu_Lys_Lys_Leu_Glu_Glu_Ala_Ala_Lys_Lys_Trp_Asn_Trp_ Phe (SEQ ID NO: 32)

 (q) Tyr_Thr_Ser_Leu_ne_Glu_Glu_Leu_Ile_Lys_Lys_Ser_Glu_Glu_Gln_Gln_Lys_Ly s_Asn_Glu_Glu_Glu_Leu_Lys_Lys_Leu_Glu_Glu_Trp_AlaT

 (r) Tyr_Thr_Ser_Leu- Ile_Glu_Glu_Leu- Ile_Lys_Lys_Ser_Glu_Glu_Gln_Gln_Lys_Lys _Asn_Glu_Glu_Glu_Leu_Lys_Lys_Leu_Glu_Glu_Trp_AlaTrp_ys_Lrp_A

 (s) Tyr_Thr_Ser_Leu- Ile_Lys_Lys_Leu- Ile_Glu_Glu_Ser_Lys_Lys_Gln_Gln_Glu_Glu _Asn_Glu_Glu_Glu_Leu_Lys_Lys_Leu_Glu_Glu_Trp_AlaTrp_ys

 (t) Tyr_Thr_Ser_Leu- Ile_Glu_Glu_Leu- Ile_Lys_Lys_Ser_Lys_Lys_Gln_Gln_Glu_Glu _Asn_Lys_Lys_Glu_Leu_Glu_Glu_Leu_Glu_Glu_Trp_AlaTrp_Lrp_H

 (u) Tyr_Thr_Ser_Leu_ne_Glu_Glu_Leu_Ile_Lys_Lys_Ser_Lys_Lys_Gln_Gln_Glu_Gl u_Asn_Glu_Glu_Glu_Leu_Lys_Lys_Leu_Lys_Lys_Trp_Ala_Trp_lu_he

 (v) Tyr_Thr_Ser_Leu- Ile_Lys_Lys_Leu- Ile_Glu_Glu_Ser_Glu_Glu_Gln_Gln_Lys_Lys _Asn_Glu_Glu_Glu_Leu_Lys_Lys_Leu_Lys_Lys_Trp_AlaTrp_lu_p

 The polypeptide according to any one of claims 5 to 7, which has an amino acid sequence of either (w) or (x) below.

 (w) Leu_Asp_Ala_Asn_Ile_Thr_Lys_Leu_Leu_Glu_Glu_Ala_Gln_Ile_Gln_Gln_Glu_L ys_Asn_Met_Tyr_Glu_Leu_Gln_Lys_Leu_Asn_Gln_Trp_hepT

 (x) Leu_Asp_Ala_Asn_ne_Glu_Glu_Leu_Leu_Lys_Lys_Ala_Glu_Glu_Gln_Gln_Lys_L ys_Asn_Glu_Glu_Glu_Leu_Lys_Lys_Leu_Glu_Glu_ i, rp_Asp_Ler_LL_ys

Claim 1 ~: The polypeptide according to any one of LOs or a pharmaceutically acceptable salt thereof. Anti-HIV agent contained as an active ingredient.

[12] A pharmaceutical composition comprising the anti-HIV agent according to claim 11 together with a pharmaceutically acceptable carrier or additive.

 [13] The anti-HIV agent according to [11], wherein the polypeptide or a pharmaceutically acceptable salt thereof is contained in an amount of 0.01 to 10 mg per kg of body weight per day for an adult.

 [14] A method for treating HIV, comprising administering an effective amount of the polypeptide according to any one of claims 1 to 10 to an HIV patient.

 [15] Use of the polypeptide according to claim 1 to 10 for producing a composition for treating HIV.