FR2968663A1 - PEPTIDES AND ANTIVIRAL DRUG - Google Patents

Abstract

The present invention relates to peptides for inhibiting the replication of the HIV virus and comprising the sequence X X X X X wherein: X is selected from the group consisting of KKVKF, KKVKW, KKVKY, KVKW, KVKY, KVKF, KKF, KKW and KKY; X is selected from the group consisting of T, R, TR, TR, RR, ARR, TAR, TARR, TAAR, TARA, TARRA, TAARR, TARAR, TAAARR, TARAAR, TARRAA, AATARR and AATAAR; X is selected from the group consisting of GW, GW, W, AW and AW; X is nothing or selected from the group consisting of GR, AR, A, R and G; X is selected from the group consisting of MK, QMK, QMKK, NMK and NMKK; cysteine residues may optionally be inserted into said sequence for its cyclization. The present invention also relates to the use of these peptides as a medicament. The present invention finds applications in the treatment of AIDS and in the research and diagnosis of HIV.

Description

TECHNICAL FIELD The present invention relates to peptides for combating the replication of the HIV virus and to their use as a medicament. The present invention finds applications in the treatment of AIDS and in the research and diagnosis of HIV.

In the description below, references in brackets ([]) refer to the list of references at the end of the examples.

STATE OF THE ART The pandemic caused by the HIV-1 virus (Human Immunodeficiency Virus type 1) is one of the major problems of public health in the world. This pandemic is especially dramatic in developing countries, where treatment costs prevent the control of this pandemic. In some parts of Africa, infection rates of up to 50% are observed, completely disrupting the socio-economic life of these regions. De Clercq takes stock of current therapies (http://www.aidsmeds.com/list.shtml [1]). HIV treatment currently relies on a combination of molecules targeting the three enzymes of the virus: reverse transcriptase (RT), protease (PR) and integrase (IN). There is also an inhibitor of the fusion of the virus to the target cells, but of very limited use. There is no vaccine solution against this virus to date, despite the many trials, including that of Merck (Bradac K, Dieffenbach CW.) HIV vaccine development: Lessons from the past, informing the future IDrugs, 2009 Jul; ): 435-9 [2]).

In addition, several classes of molecules targeting the NCp7 protein have also been developed. Current NCp7 inhibitors aim to eject zinc atoms (Rice et al, 1993 [3], Rice et al, 1995 [4]). Recent reviews (de Rocquigny et al, 2008 [5] and Goldchmidt et al., HIV therapy 2010 [6]) provide a detailed description of the approaches developed to date against the protein of the nucleocapsid, and describe the principles and limits these approaches, in particular the lack of specificity, which have not yet made it possible to use these molecules in therapy. 1 o The major problem of the AIDS virus is its great genetic variability. Mutations of the virus occur at a very high frequency, especially at the level of the enzymes of the virus, generating resistance to antivirals. To limit the appearance of resistance, antivirals are used in combination so-called tritherapies, targeting several enzymes by different mechanisms. Nevertheless, resistances are more and more frequently observed, forcing the clinician to change treatments. In addition, there is currently no treatment that can be administered at low doses, as described at http://www.aidsmeds.com/list.shtml [1]. In addition, the drugs used frequently cause significant side effects. The current means of combating the HIV-1 virus have many other drawbacks, such as the toxicity of the drugs targeting RT, RA and IN, a largely incomplete specificity, the cost and the difficulty of producing the drugs, etc. There is therefore a real need to develop new means of fighting against the HIV-1 virus overcoming these defects, disadvantages and obstacles of the prior art. In particular, efficient, non-cytotoxic compounds which can be used at low concentration, do not require high production costs, can be developed which can be used alone or in addition to existing therapies.

Description of the Invention The present invention specifically addresses the aforementioned problems of the prior art by providing peptides for effectively controlling replication of the HIV virus. Thus, the subject of the present invention is in particular a peptide comprising the sequence XaXbXcXdXe in which: Xa is chosen from the group comprising KKVKF (SEQ ID NO: 317), KKVKW (SEQ ID NO: 318), KKVKY (SEQ ID NO. 319), KVKW (SEQ ID NO: 320), KVKY (SEQ ID NO: 321), KVKF (SEQ ID NO: 322), KKF, KKW and KKY; Xb is selected from the group consisting of T, R, TR, RR, ARR, TAR, TARR (SEQ ID NO: 323), TAAR (SEQ ID NO: 324), TARA (SEQ ID NO: 325), TARRA (SEQ ID NO. ID NO: 326), TAARR (SEQ ID NO: 327), TARAR (SEQ ID NO: 328), TAAARR (SEQ ID NO: 329), TARAAR (SEQ ID NO: 330), TARRAA (SEQ ID NO: 331). AATARR (SEQ ID NO: 332) and AATAAR (SEQ ID NO: 333); Xc is selected from the group consisting of GW, GWD, W, AW and AWD; Xd is nothing or selected from the group consisting of GR, AR, A, R and G; and Xe is selected from the group consisting of MK, QMK, QMKK (SEQ ID NO: 334), NMK and NMKK (SEQ ID NO: 335). In this sequence, unless otherwise indicated, the letters determining the sequence of the peptide according to the invention correspond to the abbreviation for a letter proposed by Leder (Leder et al., Introduction to Molecular Medicine, Ed Sientific American, 1994 [7]). WD stands for D-tryptophan. In the peptide according to the present invention, Xa may for example be selected from the group consisting of KKVKF (SEQ ID NO: 317), KKVKW (SEQ ID NO: 318), KVKW (SEQ ID NO: 320) and KVKF (SEQ ID NO. 322).

In the peptide according to the present invention, Xb may for example be selected from the group consisting of RR, ARR, TARR (SEQ ID NO: 323), TARRA (SEQ ID NO: 326), TAARR (SEQ ID NO: 327), TARAR (SEQ ID NO: 328), TAAARR (SEQ ID NO: 329), TARRAA (SEQ ID NO: 331), and AATARR (SEQ ID NO: 333). For example, Xb may be selected from the group consisting of TARR (SEQ ID NO: 323) and AATARR (SEQ ID NO: 333). In the peptide according to the present invention, Xc may for example be selected from the group comprising GW and W. In the peptide according to the present invention, Xd may for example be nothing or GR. In the peptide according to the present invention, xe may for example be selected from the group consisting of QMK, QMKK (SEQ ID NO: 334) and MK. In the peptide sequence according to the present invention, K may be replaced by R. Independently, V may be replaced by M, L or I. The amino acids of the peptide sequence according to the invention are generally L-shaped, but can be for example in D form. In addition, the amino acids of the peptide sequence according to the invention can be methylated. The peptide according to the present invention may further comprise 1 or 2 Cysteine residues (C). These cysteine residues can be integrated at any point in the sequence. Examples of peptides according to the invention are shown in the following table: Table 1: Examples of peptides according to the present invention SEQ Amino acid sequences ID NO. 1 CKKFAATAARGWQMKC 2 CKKVFTARRGWQMKKC 3 CKKVFTGWGRQMKC 4 CKKVFTRGWQMKC 5 CKKVKFTARRGWGRQMKKC SEQ Amino Acid Sequences ID NO. 154 KKYCRRGWGRNMKC 155 KKYCTAAARRGWGRQMKC 156 KKYCTAAARRWQMKKC 157 KKYCTARRAAGWGRCQMKK 158 KKYFCTARGWGRQMKC 6 CKKVKFTARRGWQMKKC 7 CKKVKYTARRAGWQMKKC 8 CKKVKYTARRGWQMKC 9 CKKVKYTARRWGRQMKC 10 CKKVKYTRGWGRCQMK 11 CKKWAATAARGWGRCQMK 12 CKKWFTARGWGRQMKC 13 CKKWRGWGRCQMKK 14 CKKYFTARWGRQMKC 15 CKKYRGWGRQMKC 16 CKKYRRGWGRQMKKC 17 CKKYRRWQMKC 18 CKVKFTARARGWQMKC 19 CKVKFTARRAAGWQMKC 20 CKVKFTARRAGWGRQMKC 21 CKVKFTARRAGWQMKC 22 CKVKFTARRAGWQMKC 23 CKVKFTARRGWCQMK 24 CKVKFTARRGWGRMKC 25 CKVKFTARRGWMKC 26 CKVKYTGWQMKKC 27 KCKVKFTARRGWQMKKC 28 KCKYTARRGWCGRQMKK 29 KKCFTAAARRGWGRCQMK 30 KKCFTAAARRGWGRQMKC 31 KKCVKFTARRGWGRCQMKK 32 KKCKFTARRGWCGRQMKK 33 KKCVKWTAAARRWARCQMK 34 KKCVKWTARAARWGRQMKC 35 KKCVKYARRGWGRCQMK 36 KKCWTAARGwGRQMKKC 37 KKCYAATAARGwCGRQMK 38 KKCYTAARGWGRQMKKC 39 KKFAATAARGWGRQMK 40 KKFAATAARGWQMK 41 KKFARRGWGRQMKK 42 KKFARRGWQMK 43 KKFARRWARQMK 44 KKFCRGWQMKC 45 KKVKFTARRGWGRQMKK 46 KKCKFTARRGWGCRQMKK 47 KKFFTARGWGRQMK 48 KKFFTARGWQMK 49 KKFFTARWGRQMK 50 KKFTAAARRGWGRQMK 51 KKFT AAARRWGRQMKK 52 KKFTARRAWARQMKK 53 KKFTARRAwGRQMK 159 KKYFTARGWGRQMK 160 KKYFTARGWQMK 161 KKYRGWGRQMK 162 KKYRRGWGRNMK 163 KKYTAAARRGWGRQMK 164 KKYTAAARRWQMKK 165 KKYTAARGWGRQMK 166 KKYTAARGWGRQMKK 167 KKYTAARGwGRQMKK 168 KKYTARRAAGwGRQMK 169 KKYTARRAAGWGRQMKK 170 KKYTARRAWGRQMKK 171 KKYTARRGWGRQMKK 172 KKYTARRGWQMK 173 KKYTGWARQMK 174 KKYTRGWQMK 175 KVCKFRGWQMKC 176 KVCKFTARAGWCQMK 177 KVCKWFCTARGWCQMKKC 178 KVCKWTAARWRCQMKK 179 KVCKYTRGWQMKC 180 KVKCFARRGWCQMK 181 KVKCWAATAARGWQMKC 182 KVKCWTARAGWCQMK 183 KVKFAATARRGWGRQMK 184 KVKFAATARRGWQMK 185 KVKFARRGWGRQMK 186 KVKFARRGWQMK 187 KVKFCAATARRGWQMKC 188 KVKFCTAARGWQMKC 189 KVKFCTAARRGWCGRQMK 190 KVKFCTAARRGWQMKC 191 KVKFCTARAARGWCGRQMK 192 KVKFAATARRGWQMK 193 KVKFARRGWQMK 194 KVKFCTARAARGWCQMK 195 KVKFCTARRGWGRCQMK 196 KVKFTAARGWQMK 197 KVKFCTARRWGRCQMK 198 KVKFCTARRWQMKC 199 KVKFCAATARRGWQMKC 200 KVKFRGWGRQMK 201 KVKFRGWQMK 202 KVKFTARAARGWQMK 203 KVKFTAAARRGWQMK 204 KVKFRRGWGRQMK 205 KVKFRRGWQMK 206 KVKFTAAARRGWGRQMK 4 KKFCTARRGWGR CQMK 55 KKFTARRGWGRQMK 56 KKFTARRGWQMKK 57 KKFTCARRAGWGRCQMK 58 KKFTGWGRQMK 59 KKFTRGWQMKK 60 KKVCKWRGWGRCQMK 61 KKVCKWRRWARQMKKC 62 KKVCKWTARRAGWGRCQMK 63 KKVFAATAARGWGRQMK 64 KKVFAATARRAwRQMK 65 KKVFARRGWQMKK 66 KKVFARRWGRQMKK 67 KKVFCARRAwGRCQMK 68 KKVKFCARRGWCRQMKK 69 KKVKFCARRGWGCRQMKK 70 KKVFRGWGRQMK 71 KKVFRGWGRQMKK 72 KKVFRRGWGRNMKK 73 KKVFTARRAGWGRQMKK 74 KKVFTARRGWGRQMK 75 KKVFTARRGWQMKK 76 KKVFTGWGRQMK 77 KKVFTRGWQMK 78 KKVKCFTARRGWGCRQMKK 79 KKVKCFTARRGWGRQMKKC 80 KKVKCFTARRGWQCMKK 81 KKVKFCTARRGWCRQMKK 82 KKVKFCTARRGWGRQMKKC 83 KKVKFTARRGWGRQMKK 84 KKVKFTARRGWQMKK 85 KKVKWAATAARGWGRQMK 86 KKVKWAATAARGWQMK 87 KKVKWAATARRGWMK 88 KKVKWAATARRWGRQMK 89 KKVKWARRGWGRQMK 90 KKVKWARRGWQMK 91 KKVKWARRGwRQMK 92 KKVKWCAATAARGWGRQMKC 93 KKVKWCTAARGWGRCQMKK 94 KKVKWFTARGWGRQMKK 95 KKVKWFTARGWRQMK 96 KKVKWFTARWQMK 97 KKVKWRGWGRQMK 98 KKVKWTARAARWGRQMK 99 KKVKWTARARGWGRQMK 100 KKVKWTARRAAGWGRQMKK 101 KKVKWTARRAAGWQMK 207 KVKFTAAARRGWQMK 208 KVKFTAARCGWGRQMKC 209 KVKFTAARGWGRQMK 210 KVKFAR RGWQMK 211 KVKFTARGWQMK 212 KVKFTAARGWQMK 213 KVKFTAARRGWGRQMK 214 KVKFTAARRGWQMK 215 KVKFTARARGWQMK 216 KVCKFRGWQMKC 217 KVKFRRGWQMK 218 KVKFTARAARGWGRQMK 219 KVKFTARAARGWQMK 220 KVKFRGWQMK 221 KVKFTARAGWGRQMK 222 KVKFTARAGWQMK 223 KVKFTARARGWGRQMK 224 KVKCFTAAARRGWCGRQMK 225 KVKFARRGWQMK 226 KVKFTARARGWQMK 227 KVKFTARGWGRQMK 228 KVKFTARGWQMK 229 KVKFTAARRGWQMK 230 KVKFTARRAAGWGRQMK 231 KVKFTARRAAGWQMK 232 KVKFTARRAGWGRQMK 233 KVKFTARRAGWQMK 234 KVKFTARRWQMK 235 KVKFTARRGKGwGRQMKK 236 KVKFTGWQMK 237 KVKFTARRGKWGRQMKK 238 KVKFTARRGWGGRQMKK 239 KVKFTARRGWGRMK 240 KVKFTARRGWGRQMK 241 KVKFTARRGWMK 242 KVKWCTARRGWQMKC 243 KVKFTARRAGWQMK 244 KVKFTARRGWMK 245 KVKFTRGWQMK 246 KVKFTARRGWQMK 247 KVKFTARRWGRQMK 248 KVKFTARRWQMK 249 KVKFTGWGRQMK 250 KVKFTGWQMK 251 KVKFTRGWGRQMK 252 KVKFTRGWQMK 253 KVKWTARRGWQMK 254 KVKWAATAARGWGRQMK 102 KKVKYAATARRGwQMK 103 KKVKYARRGWGRQMK 104 KKVKYARRGWGRQMK 105 KKVKYTAAARRGWGRQMK 106 KKVKYTARRAGWGRQMKK 107 KKVKYTARRAGWQMK 108 KKVKFTARRGWQMKK 109 KKVKYTARRGWGRQM K 110 KKVKYTARRGWQMK 111 KKWAATARRGWQMK 112 KKWAATARRWGRQMK 113 KKWARRGWGRQMKK 114 KKWARRGWQMKK 115 KKWARRWAQMK 116 KKWCAATARRGWGRCQMKK 117 KKWCAATARRWGRCQMK 118 KKWCARRGWCQMKK 119 KKWCARRGWGRQMKKC 120 KKWCRRGwGRQMKC 121 KKWCRRGWQMKC 122 KKWCTAAARRAwGRCQMK 123 KKWFTARAWGRQMK 124 KKWFTARGWGRQMK 125 KKWFTARGWQMK 126 KKWRGWGRQMKK 127 KKWRGWQMK 128 KKWRRGWQMK 129 KKWTAAARRAwGRQMK 130 KKWTAAARRGWGRQMK 131 KKWTAAARRGWQMK 132 KKWTAARCGWGRQMKKC 133 KKWTAARGWGRQMK 134 KKWTAARGwGRQMKK 135 KKWTAARRGWQMK 136 KKWTARAARGWQMK 137 KKWTARARGWGRQMK 138 KKWTARARGWQMK 139 KKWTARARGWQMK 140 KKWTARARWGRQMK 141 KKWTARRAAGWGRQMKK 142 KKWTARRAAWGRQMK 143 KKWTARRGWGRQMK 144 KKWTARRGWGRQMKK 145 KKYAATAARGWQMK 146 KKYARRGWGRNMKK 147 KKYARRGWGRQMK 148 KKYARRGWQMK 149 KKYARRGWQMKK 255 KVKWAATAARGWQMK 256 KVKWAATARRGWGRQMK 257 KVKWAATARRGWQMKK 258 KVKFTARRAAGWQMK 259 KVKFTARRGKGWG RQMKK 260 KVKFTARRGWQMK 261 KVKWARRGWGRQMK 262 KVKWARRGWQMK 263 KVKWARRWARQMK 264 KVKWARRWGRQMKK 265 KVKWCTARARGWCGRQMK 266 KVKWCTARARGWC QMKK 267 KVKWCTARRGWCGRQMK 268 KVKWCTARRGWQMKC 269 KVKWFTARAwGRQMK 270 KVKWFTARGWGRQMK 271 KVKWFTARGWQMKK 272 KVKWRGWAQMKK 273 KVKWRGWGRQMK 274 KVKWRRAwGRQMK 275 KVKWTAAARRGWQMKK 276 KVKWTAARGWGRQMK 277 KVKWTAARRGwQMK 278 KVKWTAARWRQMKK 279 KVKWTARAARGWGRQMK 280 KVKWTARAARGWQMK 281 KVKWTARAGWQMK 282 KVKWTARARGWGRQMK 283 KVKYARRGwQMK 284 KVKWTARARGWQMKK 285 KVKWTARRAAGWGRQMKK 286 KVKWTARRAAGWQMK 287 KVKWTARRAAwGRQMKK 288 KVKWTARRAGWGRQMK 289 KVKWTARRAGWGRQMKK 290 KVKWTARRGWGRQMK 291 KVKWTARRGWQMK KVKWTARRWQMK 292 293 294 KVKWTCAARRGWCQMKK KVKWTGWGRQMK KVKYAATAARWQMK 295 296 297 KVKYARRGwQMK KVKYARRGWQMK KVKYCRRWGRQMKC 298 299 300 KVKYFTARGWGRQMK KVKYFTARGWQMKK KVKYRGWGRQMK 301 302 150 KVKYRGWQMKK KKYARRWARQMK KVKFTARRGKwGRQMKK 151 152 153 KVKFTARRGwGRQMKK KVKFTARRGWGRQMKK 303 KVKYRRGWGRNMK KVKYRRWGRQMK 304 305 306 KVKYTAARWARQMKK KVKYTARAARGWGRQMK The present invention is of course not limited to sequences presented in Table 1 above.

The peptide according to the invention may be linear or cyclic. When the peptide according to the invention is linear and comprises one or two cysteine residues, the cysteine residues may be protected by any means known to those skilled in the art. For example, cysteine residues may be protected by methylation, acylation, or formation of disulfide bridges. Examples of linear peptides are shown in Table 1 above. According to the invention, cysteine residues may optionally be integrated in said sequence. Preferably, the cysteine residues may be integrated into a peptide according to the invention during the synthesis of said peptide. The peptide according to the invention may for example be chosen from SEQ ID NO. 1 to 306. These may be for example the peptides shown in Tables 2 and 6 to 9 below. The preferred peptides according to the invention are those having a relative inhibitory activity greater than 1.5, preferably greater than 2.5, preferably greater than 3.5. When the peptide according to the invention is cyclic, the cyclization can, for example, be carried out by a bond between the C-terminal and N-terminal ends of the peptide as presented by Tulla-Puche and Barany (Judith Tulla-Puche and George Barany "On-Resin Native Chemical Ligation for Cyclic Peptide Synthesis", J. Org Chem., Vol 69, pp. 4101-4107, 2004 [8]). For example, all the sequences shown in Table 1 above can be cyclized via cysteine residues present or added in a peptide according to the invention.

When two cysteine residues are present or integrated in the sequence of the peptide according to the invention, they are preferably at a distance allowing cyclization of the peptide, said cysteine residues being connected to one another via their free -SH group, that is to say say by means of an intramolecular disulfide bridge, or a spacer arm. Among these, experiments were carried out on cyclized peptides via an intramolecular disulfide bridge and on cyclized peptides via a spacer arm presented respectively in Tables 8 and 9 below.

For example, the two cysteine residues can be integrated with 4 amino acids apart, for example 5 amino acids apart, for example 6 amino acids apart, for example 7 amino acids apart, for example 8 amino acids apart, for example 9 amino acids apart, for example 10 amino acids apart, for example 11 amino acids apart, for example 12 amino acids apart, for example 13 amino acids apart, for example 14 amino acids apart, for example 15 amino acids apart, for example 16 amino acids apart, for example 17 amino acids apart, for example at 18 amino acids apart, for example at 19 amino acids apart. The two cysteine residues may, for example, be present or integrated in the N- or C-terminal ends of the peptide according to the invention. The cysteine residues can also be integrated between Xa and Xb, Xb and Xc, Xc and Xd, Xd and Xe or Xc and Xe, or in Xa or Xb. Preferably, when two cysteine residues are integrated in the sequence of a peptide according to the invention, one is integrated between Xa and Xb and the other is integrated between Xc and Xd or Xd and xe. The term "disulfide bridge" means a covalent bond which, by oxidation, combines the thiol functions of two cysteines. When the disulfide bridge is made from two cysteines of the same amino acid sequence, it is called "intramolecular disulfide bridge". Examples of cyclic peptides whose ring is formed via an intramolecular disulfide bridge, according to the present invention, are shown in Table 9 below. The term "spacer arm" means any molecule for connecting two amino acids of the peptide sequence according to the invention. For example, the spacer arm makes it possible to connect two cysteine residues of the peptide sequence according to the invention. In the present, the spacer arm can also be called "LINKER" or "li". The spacer arm may, for example, be selected from the group consisting of C 1 -C 6 alkyl and a compound selected from the compounds of the formula: CH 2 CH 2 CH 3 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 (CH) CH 2 --CH 2 --CH 2 - (CH 2) n (CH 2) n

- (CH2CH2O) n-CH2CH2-

wherein n is an integer from 0 to 10, m is an integer from 0 to 10 and X is selected from the group consisting of oxygen, sulfur, CH2, NH and an NCH3 group. In the formulas of the abovementioned spacer arms, the "free" ends, for example the CH 2 - or S - groups, are bonded with the sulfur atom of the cysteine residues of the peptide according to the invention. The spacer arm can connect two amino acids of the peptide sequence according to the invention by any means known to those skilled in the art. For example, the protocol described in Balraju et al. (2005) [9] and in Litovchick et al. (2008) [10]. The peptide according to the invention may be associated with any substance that allows or facilitates its penetration into a cell. For example, the peptide according to the invention may comprise, at its carboxy-terminal end, a signal peptide. It can be any signal peptide well known to those skilled in the art (Von Heijne G. et al., "Locating proteins in the cell using TargetP, SignalP, and related tools", Nature Protocols, vol 2, pages 3569 -3571, 2007 [11]). For example, the signal peptide may be selected from the sequences comprising SQPKRRKK (SEQ ID NO: 307), SKL, KDEL (SEQ ID NO: 308), PPKKKRV (SEQ ID NO: 309), MMSFVALLLVGILFWAWEAEQLTKCEVFQ (SEQ ID NO: 310). ), MLSLRQSIRFFKCSSRYLL (SEQ ID NO: 311) and ALWRALWFRLWRLAWFRLWR (SEQ ID NO.312). The peptide according to the invention may for example also be associated with a cell penetration peptide (CPP). For example, the peptide according to the invention is associated with the CPP at its carboxy terminal end. For example, the CPP may be a sequence selected from the group consisting of Ac-ALWRALWFRLWRLAWFRLWR-Cya (NanoVepep, SEQ ID NO: 312), Ac-KETWWETWWTEWSQPKKKRKV-Cya (Pep-1, SEQ ID NO: 336), Ac-KETWFETWFTEWSQPKKKRKV -Cya (Pep-2, SEQ ID NO: 313) and Ac-KWFETWFTEWPKKRKV-Cya (Pep-3, SEQ ID No. 314) (Morris MC, Deshayes S, Heitz F, Divita G, Cell-penetrating peptides: from molecular mechanisms to therapeutics, Biol Eye (2008) 100, 201-217 [12]). Preferably, the CPP is SEQ ID NO.312.

The signal peptide or the CCP can be attached to any peptide according to the invention. Experiments showing the effectiveness of these peptides are shown in Table 7. The signal peptide or CPP can for example be synthesized chemically, for example by solid support chemical synthesis. It may be for example a synthetic method in Fmoc chemistry, such as that described in "Fmoc Solid Phase Peptide Synthesis: A Practical Approach (Practical Approach Series) WC Chan (Editor), Peter D. White (Editor) "Oxford University Press 2000" [13] The signal peptide or the CPP peptide may be combined with the peptide according to the invention by any means known to those skilled in the art, for example a signal peptide may be associated with a peptide according to the invention by synthesis of an amino acid sequence corresponding to the succession of the sequence of a signal peptide and the sequence of a peptide according to the invention For example, a peptide CPP may be associated to a peptide according to the invention by synthesis of an amino acid sequence corresponding to the CPP peptide and combination of the latter with the sequence of a peptide according to the invention.

The peptide according to the present invention is directed against an HIV-1 protein that is not targeted in current therapies. This is the nucleocapsid NCp7. In the present, NCp7 nucleocapsid is also referred to as "NCp7 protein", "NCp7" or "NC". The nucleocapsid NCp7 protein of HIV-1 is composed of two highly conserved zinc fingers. This protein plays a crucial role in several key stages of the HIV virus cycle, especially during the two strand breaks during reverse transcription. The functions of the nucleocapsid rely largely on its chaperone properties which appear highly dynamic (Darlix J. L. et al., J. Mol Biol, 254.523, 1995 [14], Levin et al., 2005 [15]). The importance of the NCp7 protein is illustrated by the total loss of infectivity following point mutations altering the globular structure of zinc fingers (Demene et al., Biochemistry, vol 33 pages 11707, 1994 [16], Dorfman et al. J, volol 67, page 6159, 1993 [17], Gorelick et al., J. Virol, vol 73, page 8185, 1999 [18], Gorelick et al., J. Virol, vol 64, page 3207, 1990 [19] and Tanchou et al [20]). This basic protein plays a critical role in the viral cycle, mainly by chaperoning transconformations of the viral genome required during the replication of the virus, especially during retrotranscription. Reverse transcription is a key step in the replicative cycle of HIV-1, in which single-stranded genomic RNA is converted to double-stranded proviral DNA. This step is catalyzed by the reverse transcriptase (or reverse transcriptase) and its effectiveness and especially its specificity increase under the action of the nucleocapsid protein p7 (NC or NCp7). The inventors are the first to have developed effective NCp7 competitors that can inhibit viral replication. These competitors are the peptides of the present invention. The peptides according to the invention have made it possible to inhibit the production of the virus by Ti lymphocytes at doses up to a few nanomolar while AZT, one of the reference compounds, directed against the reverse transcriptase is active only at micromolar doses in the same test. The present invention also relates to a peptide according to the invention for use as a medicament. Preferably, the drug is an anti-retroviral.

More preferably, the drug is an anti-HIV. More preferably, the drug is an anti-HIV-1. For example, the peptide of the present invention can be used as a medicine for the treatment of AIDS. For example, the peptide of the present invention can be used as a drug for the treatment of AIDS resulting from HIV infection, for example HIV-1.

The peptide alone or a mixture of peptides according to the invention can be used. For example, the peptide mixture may comprise 2 peptides according to the invention, for example 3, 4, 5, 6, 7, 8, 9 or more than 9 peptides according to the invention. A combination of the peptides according to the invention can indeed make it possible to further increase the anti-retroviral action. The peptide according to the invention may be used as a medicament alone, that is to say in mono-therapy, or in the context of a bi-therapy, a tri-therapy or a quadri-therapy. therapy, that is to say associated with other treatments, with other active molecules. In other words, the peptide according to the present invention can be used alone or in combination with any known treatment for controlling HIV. According to the invention, the term "used in combination" means a use of the peptide according to the invention jointly or simultaneously, concomitantly or sequentially, with any known treatment for combating HIV. The mode of administration may be identical or different depending on the co-administered molecules. "Joint or simultaneous" means the use of the peptide according to the invention with any known treatment for combating HIV in a single composition containing them. The term "concomitant" means the separate use of the peptide according to the invention and any known treatment for controlling HIV, by the same or different administration routes during the same period of administration. By "successive" is meant the separate use of the peptide according to the invention and any known treatment for the control of HIV, by the same or different administration routes during different periods of administration.

The term "administration period" refers to the time during which a treatment is administered. It may, for example, be several days, for example two days, three days, four days, etc., for example one or more weeks, for example a week, two weeks, three weeks, etc., for example a or several months, for example one month, two months, three months, etc., for example one or more years, for example one year, two years, three years, etc. For example, the peptide according to the invention can be used in combination with at least one antiretroviral. In other words, the peptide according to the invention can be used as a medicament, said medicament further comprising at least one antiretroviral. According to the invention, the antiretroviral may for example be chosen from the group comprising: AZT, lamivudine, emtricitabine, didanosine, stavudine, abacavir, zalcitabine, tenofovir, racivir, amdoxovir, apricitabine, elvucitabine, efavirenz, nevirapine, etravirine, delavirdine , rilpivrin, tenofovir, fosalvudine, amprenavir, tipranavir, idinavir, saquinavir, fosamprenavir, ritonavir, darunavir, atazanavir, nelfinavir, kaletra, raltegravir, elvitegravir, MK-2048, enfuvirtide, vicriviroc, TNX-355 and bevirimat. For example, the peptide of the invention may be used in combination with a combination of antiretrovirals selected from the group consisting of: zidovudine + lamivudine; abacavir + lamivudine; tenofovir + emtricitabine; abacavir + lamivudine; abacavir + lamivudine + zidovudine; tenofovir + emtricitabine + efavirenz. The peptide according to the invention used as a medicament may be in any suitable form of administration. It may be one of the forms known to those skilled in the art to deliver an active molecule that is a peptide (Peppas NA, Carr DA, Chemical Engineering Science, 64, 4553-4565 (2009) [21]; Morishita M, Peppas NA, Drug Discovery Today, 11, 905-910 (2006) [22]).

The peptide according to the present invention may, for example, be intended for oral administration or injection. Preferably, the peptide according to the invention may be in injectable form.

In this case, the peptide according to the invention can be packaged in any form known to those skilled in the art to be administered by injection. It can be for example a bottle or a bulb. For example, the injection may be an intramuscular, intravenous or intraperitoneal injection. In the case of oral administration, the peptide may be in the form of a capsule, a free powder, a lyophilizate, a granule, a minigranule, a microgranule, a soft-shell capsule or a hard-shell capsule. , uncoated tablet, coated tablet, effervescent tablet, soluble tablet, dispersible tablet, orodispersible tablet, solution, emulsion or suspension. The peptide according to the invention may be combined with a pharmaceutically acceptable excipient, adjuvant or carrier. The term "excipient, adjuvant or pharmaceutically acceptable carrier" means any substance for diluting or transporting the peptide according to the invention. Preferably, the pharmaceutically acceptable excipient does not affect the effectiveness of the peptide. The pharmaceutically acceptable excipient or adjuvant may be any substance known to those skilled in the art for administering a small peptide. When the excipient is an aqueous solution this may be, for example, any of the solutions presented in Heitz et al., 2009 (Twenty years of cell-penetrating peptides: from molecular mechanisms to therapeutics, Heitz F, Morris MC , Divita G. Br J Pharmacol 2009 May; 157 (2): 195-206 [23]) or in Wehrle P. (Wehrle P., Galenic Pharmacy, Pharmaceutical Formulation and Technology, 2007 [24]). When the excipient is an emulsion, it can be a water-in-oil emulsion, oil in water, water-in-oil in water (Wehrle P. [24]).

When the excipient is an excipient allowing the formation of a capsule, a free powder, a lyophilizate, a granule, a minigranule, a microgranule, a soft-shelled capsule, d a hard shell capsule, an uncoated tablet, a coated tablet, an effervescent tablet, a soluble tablet, a dispersible tablet, an orodispersible tablet, a solution, a an emulsion or a suspension. It may be for example any excipient known to those skilled in the art to manufacture these formulations. It may be for example an excipient presented in Wehrle P. [24]. The peptide of the present invention may be administered as a drug, preferably in an amount sufficient to combat HIV.

The synthesis of the peptide according to the present invention can be carried out by any method known to those skilled in the art. This may be for example a chemical synthesis or genetic engineering.

Preferably, given the small size of the sequences of the peptides according to the invention, the peptides can be synthesized chemically, for example by chemical synthesis on a solid support. It may be for example a synthesis process in Boc and / or Fmoc chemistry.

Thus, the subject of the present invention is also a method for synthesizing a peptide according to the invention, said method comprising a synthesis step in Boc chemistry and / or in Fmoc chemistry. For example, the method described in "Fmoc Solid Phase Peptide Synthesis: A Practical Approach (Practical Approach Series)" W.Chan Chan (Editor), Peter D. White (Editor) ", Oxford Univ Press 2000" [13] can be used.

When the synthesis of the peptide according to the invention is carried out by genetic engineering, it is possible, for example, to construct a large peptide comprising the peptide of the present invention and to digest it with restriction enzymes in order to collect the peptide of the invention. For example, the protocol described in F. Cordier-Ochsenbein et al. J. Mol. Biol. 279, 1177-1185 [25]. The peptide according to the invention is of small size, ranging from 8 to 21 amino acids. It therefore advantageously has excellent stability over time and excellent accessibility to the interaction sites. In addition, peptide synthesis methods are easy to implement and inexpensive. Other advantages may still appear to those skilled in the art on reading the examples below, illustrated by the appended figures, given for illustrative purposes. Brief Description of the Figures - Figure 1 shows the primary structure of NCp7 nucleocapsid protein. Figure 2 shows the tertiary structure of NCp7 nucleocapsid protein. FIG. 3 is a schematic representation of the destabilizing activity of NCp7 on cTAR. "D" and "Q" respectively represent a fluorophore and a fluorescence inhibitor. FIG. 4 represents a diagram respectively showing the fluorescence, expressed in arbitrary units, (a) cTAR, (b) cTAR in the presence of NCp7, and (c) cTAR in the presence of NCp7 and a peptide according to the invention ("inh"). FIG. 5 represents the titration of fluorescein-labeled cTAR ("cTAR-FI") at a concentration of 50 nanomolar (nM), in the presence of the peptides pA, pB, pC, pD or pE. In the abscissa, "[Pep]" represents the concentration of peptides, expressed in micromolar (pM). On the ordinate, "A" represents anisotropy. FIG. 6 represents the destabilizing activity of the peptides according to the invention (pA, pB, pC, pD and pE) on cTAR doubly labeled with Rhodamine 6G and Dabcyl. On the abscissa, "inh / cTAR" represents the ratio of peptides on cTAR. On the ordinate, "1/10" represents the ratio of the fluorescence intensity in the presence of peptide according to the invention to that in its absence. FIG. 7 represents the evolution of the binding of a peptide according to the invention ("INH") with cTAR or the cTAR * NCp7 complex when the INH ratio on cTAR increases. On the abscissa, "INH / cTAR" represents the ratio of peptide pE to cTAR. On the ordinate, "A" represents anisotropy. FIG. 8 represents a diagram of the interaction mechanisms between NCp7 ("NC") and the peptides according to the invention ("INH") with cTAR. "D" and "Q" respectively represent a fluorophore and a fluorescence inhibitor. FIG. 9 represents the comparison of the inhibitory activity of five peptides according to the invention (pA, pB, pC, pD, pE) on the destabilization of the cTAR / NCp7 complex. The abscissa represents the concentration of peptides ("[inh]") expressed in nanomolar (nM). The ordinate represents the residual destabilizing activity of NCp7, measured by the opening of cTAR (cTAR melt). FIG. 10 represents the percentage of binding of a peptide according to the invention to cTAR (("a)" and to the cTAR-NCp7 complex ("(b)"), and the percentage inhibition of the destabilization of cTAR by NCp7 ("(c)"). FIG. 11 represents a diagram of the competition between NCp7 and peptides according to the invention on the cTAR binding. The stars "*" indicate the connections between these different entities. FIG. 12 represents the correlation between the cTAR binding and the inhibitory activity on the destabilization of cTAR of five peptides according to the invention (pA, pB, pC, pD and pE). The binding is expressed according to the logarithm of K / KPE where K is the affinity of a given peptide for cTAR (Table 3) and KPE is the affinity of peptide E for cTAR. The inhibitory activity is expressed by the ratio [NCp7] / IC50 where [NCp7] denotes the concentration of NCp7 and IC50, the concentration of peptide which inhibits at 50% the destabilization of cTAR, induced by NCp7. "Bind" means binding and "inh" means inhibition. FIG. 13 represents three examples of cyclic peptides according to the invention. (a) represents an intramolecular cyclization via a disulfide bridge. (b) and (c) represent two examples of cyclic peptides via a linker. FIGS. 14A, 14B, 14C and 14D show the inhibition of the destabilizing activity of NCp7 by peptides (pm) according to the invention. The abscissa represents the ratio of peptide concentrations ("[inh]") to that of NCp7. The ordinate represents the ratio of the fluorescence intensity of the cTAR / NC complex in the presence of peptide to that of the complex in the absence of inhibitor. 30mM NaCl buffer; 0.2mM MgCl2; "tris" 25mM; pH = 7.4. The concentration of cTAR is 0.02 μM and that of NCp7 is 0.2 μM. Excitation wavelength = 520 nm. Figure 15 shows the effect of the peptides (p2, p10, p23) formulated with the Nanovepep vector peptide on HIV-1 lentivectors transduced in HeLa cells, in comparison with the effect of AZT. The abscissa represents the concentration of peptides in nanomolar (nM) or the concentration of AZT in micromolar (pM). The ordinate represents the percent GFP expression (GFP exp,%). FIG. 16 represents the inhibition of the production of HIV-1 in SupT1 cells by peptides according to the invention (p2, p10, p23) complexed with Nanovepep, or by a control (AZT). The abscissa represents the concentration in nanomolar peptides (nM) or the concentration of AZT in micromolar (pM). The ordinate represents the percent GFP expression (GFP exp,%).

EXAMPLES Example 1 Obtaining the Peptides According to the Invention The method used in this experiment is a solid support chemistry process. In this example, the method described in the document "Fmoc Solid Phase Peptide Synthesis: A Practical Approach (Practical Approach Series) WC Chan (Editor), Peter D. White (Editor)", Oxford Univ Press 2000 "[13 ], by an Applied Biosystems A 433 synthesizer at the Biophotonics and Pharmacology Laboratory, Illkirch, France) The principle of this Fmoc chemistry method is as follows: The solid phase chemical synthesis starts with the fixation on the solid support, a HMP resin ("4-Hydroxymethylphenoxyacetyl-4'-methylbenzyhydrylamine resin"), the first amino acid whose amine function was previously protected with a Fmoc group ("9-fluorenylmethyloxycarbonyl"). In a second step, the amine function is deprotected in using piperidine in NMP ("N-methyl-2-pyrrolidinone"), then the second amino acid whose carboxyl group was activated with a mixture HBTU / HOBt ("2- (1H-Benzotriazolse-1-yl) - 1,1,3,3-tetramethyluronium hexafluorophosphate / 1-hydroxy-benzotriazole ") is attached to the first amino acid by an amidation reaction. This step is repeated as many times as necessary until the desired sequence is obtained. Finally, all functions are deprotected using piperidine in NMP, and washed twice with NMP and methanol. The synthesized peptides are released from the solid support and deprotected by addition of a trifluoroacetic acid / water / phenol / thioanisole / ethanedithiol mixture (100/10/1/5/2).

The synthesized peptides are then filtered and precipitated with diethyl ether ("Et2O"). Purification of the synthesized peptides was performed using an HPLC chain using reverse phase columns (RF HPLC (C8 CH3CN / H2O + 0.05% TFA).) All the peptides shown in Table 2 were thus obtained.

Example 2: Preparation of labeled cTAR sequences The cTAR sequences were obtained by synthesis and purification at 0.02 mmol by HPLC (IBA GmbH Nucleic Acids Product Supply, Goettingen, Germany). The cTAR sequences were respectively labeled 5 'with rhodamine 6G (Rh6G) via an aminoalkyl with six carbon atoms and at 3' with a fluorescent quencher: Dabcyl (or 4 '- (dimethylaminophenylazo) -benzene) according to the protocol presented in particular in Li et al. (Li, JJ, X. Fang, SM Schuster and W. Tan 2000a.) Molecular Beacons: A Novel Approach to Detect Protein - DNA Interactions This work was partially supported by a US NSF Career Award (CHE-9733650) and by US Office of Naval Research Young Investigator Award (N00014-98-1- 0621) Angew Chem Int Ed Engl 39: 1049-1052 [26] Li, JJ, R. Geyer and W. Tan, 2000b Using molecular beacons Nucleic Acids Res 28: E52 [27] Li, QG, JX Liang, GY Luan, Y. Zhang and K. Wang 2000c Molecular beacon-based homogeneous fluorescence PCR assay 25 for diagnosis of infectious diseases, Analytical Sciences 16: 245-248 [28], Sokol, DL, X. Zhang, P. Lu and AM Gewirtz, 1998. Real time detection of DNA.RNA hybridization in living cells. Natl Acad Sci USA 95: 11538-43 [29], Tyagi, S. and Kramer FR, 1996. Molecular beacons: probes that fluoresce upon hybridization, Nat Biotechnol 14: 303-308 [30]). The oligonucleotide was then purified by RF HPLC followed by polyacrylamide gel electrophoresis. The purity of the labeled oligonucleotides was verified by electrospray mass spectrometry and was thus determined to be greater than 93%.

Example 3: Obtaining the NCp7 The NCp7 nucleocapsid protein was obtained according to the following protocol, described in Cornille et al. (Cornille F., Mely Y., Ficheux D., Salvignol I., Gerard D., Darlix J.-L., Fournié-Zaluski M.-C. and Roque B (1990) Solid phase synthesis of the retroviral nucleocapsid NCp10 of murine Moloney leukemia virus and related zinc-fingers in free SH forms: Influence of zinc chelation on structural and biochemical properties, Int.JP Pept.Protein Res., 36, 551-558 [31]). NC peptide (11-55) was synthesized by solid phase peptide synthesis on a 433A synthesizer (ABI, Foster City, Canada). The synthesis was carried out at a scale of 0.1 mmol using the standard fluorenylmethoxycarbonyl (Fmoc) / amino acid coupling protocol from 0.54 mmol / g of HMP resin having preloaded asparagine (ABI). At the end of the synthesis, 100 mg of Fmoc deprotected peptidylserine were isolated and washed twice with NMP. Cleavage of peptidylserine and deprotection were performed for two hours using 10 mL of a solution of trifluoroacetic acid ("TFA") containing water (5%, v / v), phenol (2, 5%, v / v), thioanisole (5%, v / v) and ethanedithiol (2.5%, v / v). The solution was concentrated by vacuum and the peptide was precipitated using ice-cold diethyl ether and then pelleted by centrifugation. The pellet was then washed with diethyl ether and stained prior to solubilization with aqueous TFA (0.05%, v / v). The purification by HPLC was carried out on a C8 column (uni-sphere 300A, 5 mm, 250 × 10, Interchim, France) in a water / acetonitrile mixture containing 0.06% of TFA with a linear gradient of 10-70% of acetonitrile during 30 minutes, and was followed by absorption at 220 nm.

EXAMPLE 4 Measurement of the destabilization of cTAR by NCp7 A test medium was carried out by mixing in distilled water: 30 mM NaCl, 0.2 mM MgCl 2 and 25 mM, Tris (trishydroxymethylaminomethane, or 2-amino-2 -hydroxymethyl-1,3-propanediol), 0.1 μM labeled cTAR obtained in Example 2 and 1 μM NCp7. Then, the pH was stabilized at 7.4 by addition of HCl. The fluorescence spectrum was recorded before and after the addition of NCp7 using FluoroMax3 and FluoroLog spectrofluorometers (Horiba, Jobin Yvon, Longjumeau) equipped with thermostated compartments according to the protocol described in Vuillemier et al. (Vuilleumier, C., Maechling-C. Strasser, Gerard D. and Y. Mely, 1997. Evidence and prevention of HIV-1 nucleocapsid protein adsorption on fluorescence quartz cells, Anal Biochem 244: 183-5 [32]).

When the cTAR sequence is in a normal conformation, i.e. in the absence of NCp7, the fluorophore and the fluorescence inhibitor are close, so that only very weak fluorescence is observed. After the addition of NCp7, the cTAR sequence is destabilized, inducing removal of the fluorophore and Dabcyl, and causing an increase in fluorescence (Figure 3).

EXAMPLE 5 Measurement of the Inhibitory Activity of the Peptides According to the Invention on the Formation of the cTAR-NCp7 Complex The inhibitory activity of 63 peptides according to the invention (Table 2) on the formation of the cTAR-NCp7 complex was tested for each peptide at concentrations of 1 μM and 10 μM.

For this, a test medium identical to that of Example 4 was prepared. 1 μM of NCp7 was then added to the medium. 126 tests were performed so that each of the 63 peptides was added to test medium at a concentration of 1 μM or 10 μM. The percentage inhibition of the formation of the cTAR-NCp7 complex was measured by fluorescence measurement at ten minutes and one hour after the addition of the peptides according to the same principle as that presented in Example 4.

The following formula was used to quantify the percent inhibition of peptides on the formation of the cTAR-NCp7 complex: Inhibition (%) = (1 - (If-Ifo) / (Ifmax-Ifo)) * 100

In this formula, Ifo, Ifmax and If respectively correspond to the intensity of the fluorescence of cTAR alone, the cTAR-NCp7 complex and the cTAR-NCp7 complex in the presence of a peptide according to the invention. Four independent measurements of the percent inhibition of cTAR-NCp7 complex formation were performed: at 10 minutes and at 1 hour at a peptide concentration of 1 μM, and at 10 minutes and at 1 hour at a concentration of 10 μM. ("R1" and "R2" values in Table 2 below). Each peptide was classified in each of the tests to determine a value "Ri" of between 1 (maximum observed efficiency) and 0 (no inhibition) according to the following formula: Ri = INC -'libre 1 -ILibre where I is the Fluorescence intensity of cTAR doubly labeled in the presence of NCp7 and the tested peptide, ILibre is the fluorescence intensity of doubly labeled cTAR in free form and INC is the fluorescence intensity of doubly labeled cTAR in the presence of NCp7 alone. The relative inhibitory activity ("R" in Table 2 below) of the peptides was obtained by summing the results of the four independent measurements obtained with 1 μM and 10 μM of each peptide. A value of "R" equal to 4 therefore corresponds to the most effective inhibitory activity of the peptides. The experimental results are shown in Table 2 below.

Table 2: Measurement of the Inhibitory Activity of the Peptides According to the Invention on the Formation of the Complex cTAR-NCp7 Peptide SEQ AI 10pM AI 1 pM R ID No. RI R2 RI R2 10min lh 10min lh KKVKFTARRGWGRQMKKx 83 1.00 1.00 1.00 1.00 4.00 KKVKFTARRGWQMKKx 84 1.00 0.97 0.92 1.00 3.89 KKFTARRGWGRQMKx 55 1.00 0.99 0.73 0.80 3.52 KVKWTARRGWGRQMKx 290 1.00 1.00 0.65 0.73 3.38 xKVKFTAARRGWGRQMKx 213 0.96 0.77 0.68 0.81 3.22 xKVKFTARARGWGRQMKx 223 0.61 0.93 0.74 0.76 3.04 xKVKFTARRAGWGRQMKx 232 1.00 0.93 0.50 0.54 2.97 KVKFTARRWGRQMKx 247 1.00 0.99 0.41 0.48 2.88 KVKFAATARRGWGRQMKx 183 1.00 0.82 0.53 0.51 2.86 KVKFTARRGWGRQMKx 240 1.00 1.00 0.27 0.32 2.59 KVKFTARRGWGRMKx 239 0.98 0.99 0.18 0.18 2.33 KVKFRRGWGRQMKx 204 0.99 0.95 0.17 0.20 2.31 KKVKFTARRGWQMKKx 108 0.86 0.62 0.33 0.36 2.17 KVKFTAARGWGRQMKx 209 0.99 0.74 0.22 0.16 2.11 KVKFARRGWGRQMKx 185 0.97 0.43 0.36 0.34 2.10 KVKFTARAARGWGRQMKx 218 0.81 0.55 0.29 0.30 1.95 KVKFTAAARRGWGRQMKx 206 0.85 0.59 0.12 0.16 1.72 KVKFTRGWGRQMKx 251 0.63 0.57 0.14 0.19 1.53 KVKFTARRGWMKx 244 0.55 0.25 0.31 0.38 1.49 KVKFTARRAAGWGRQMKx 230 1.00 0.17 0.16 0.14 1.47 KVKFTARGWGRQMKx 227 0.70 0.39 0.15 0.18 1.42 KVKFARRGWQMKx 186 0.69 0.48 0.08 0.11 1.36 KVKFTARAGWGRQMKx 221 0.62 0.34 0.16 0.21 1.33 KVKFRGWGRQMKx 200 0.71 0.42 0.11 0.08 1.32 KVKFAATARRGWQMKx 184 0.97 0.26 0.04 0.04 1.31 KVKFRRGWQMKx 217 0.75 0.40 0.05 0.00 1.20 KVKFTARRGWMKx 241 0.80 0.19 0.09 0.10 1.18 xKVKWTARRGWQMKx 291 0.48 0.49 0.10 0.09 1.16 KVKFTAAARRGWQMKx 203 0.90 0.12 0.05 0.03 1.10 KVKFAATARRGWQMKx 192 0.45 0.00 0.28 0.32 1.05 xKVKFTARARGWQMKx 215 0.27 0.37 0.18 0.18 1.00 xKVKFTAARRGWQMKx 213 0.33 0.55 0.05 0.05 0.98 KVKFTARAARGWQMKx 202 0.45 0.09 0.15 0.18 0.87 KVKFARRGWQMKx 225 0.42 0.13 0.16 0.15 0.86 KVKFTARRAGWQMKx 243 0.56 0.07 0.09 0.10 0.82 KVKFTARRWQMKx 234 0.42 0.33 0.04 0.00 0.79 KVKFTARRAAGWQMKx 231 0.35 0.22 0.11 0.10 0.78 KVKFTGWGRQMKx 249 0.28 0.00 0.21 0.21 0.70 KVKFTARRGWQMKx 260 0.54 0.00 0.04 0.08 0.66 KVKFARRGWQMKx 210 0.57 0.00 0.03 0.05 0.65 KVK FTARARGWQMKx 226 0.40 0.00 0.12 0.10 0.62 KVKFRRGWQMKx 205 0.56 0.01 0.04 0.00 0.61 KVKFTARRGWQMKx 246 0.40 0.02 0.11 0.08 0.61 KVKFTARRAAGWQMKx 258 0.44 0.00 0.08 0.08 0.60 KVKFTARRAGWQMKx 233 0.51 0.00 0.00 0.08 0.59 KVKFTAAARRGWQMKx 207 0.34 0.25 0.00 0.00 0.59 KVKFTARRWQMKx 248 0.55 0.02 0.00 0.00 0.57 KVKFTRGWQMKx 252 0.41 0.00 0.10 0.02 0.53 xKVKWTARRGWQMKx 253 0.26 0.18 0.06 0.02 0.52 KVKFARRGWQMKx 193 0.47 0.00 0.05 0.00 0.52 KVKFRGWQMKx 201 0.35 0.00 0.06 0.11 0.52 KVKFTAARRGWQMKx 229 0.44 0.00 0.02 0.01 0.47 KVKFTARGWQMKx 211 0.33 0.00 0.04 0.09 0.46 xKVKFTARGWQMKx 228 0.29 0.03 0.05 0.03 0.40 KVKFTARAARGWQMKx 219 0.40 0.00 0.00 0.00 0.40 KVKFTAARGWQMKx 196 0.22 0.00 0.10 0.07 0.39 xKVKWTARAGWQMKx 281 0.13 0.12 0.06 0.02 0.33 KVKFTARAGWQMKx 222 0.33 0.00 0.00 0.00 0.33 KVKFTAARGWQMKx 212 0.28 0.00 0.00 0.04 0.32 KVKFTGWQMKx 236 0.24 0.00 0.00 0.03 0.27 xKVKFTGWQMKx 250 0.26 0.00 0.00 0.00 0.26 KVKFRGWQMKx 220 0.18 0.00 0.04 0.02 0.24 xKVKFTRGWQMKx 245 0.10 0.00 0.01 0.00 0.11 In this table "Al 1 μM" and "Al 10 μM" correspond to the inhibitory activity of peptides at concentrations of 1 μM and 10 μM, respectively. The "x" in the peptide sequences respectively represent the amidation and acylation of the C- and N-terminal residues.

These results show that all the peptides tested, in accordance with the present invention, make it possible to inhibit the destabilization of cTAR by NCp7, even at concentrations of the order of one micromolar. EXAMPLE 6 Binding of Peptides According to the Invention The cTAR binding of the following five peptides in accordance with the present invention was measured: KKFTARRGWGRQMKx (SEQ ID No. 55), referred to as "pA", KVKFTARRWGRQMKx (SEQ ID No. 247), referred to as "pB" - KVKWTARRGWGRQMKx (SEQ ID No. 290), referred to as "pC", KKVKFTARRGWQMKKx (SEQ ID No. 84), referred to as "pD", and KKVKFTARRGWGRQMKKX (SEQ ID No. 83), referred to as "pE". For this, a test medium was made by mixing in distilled water: 30mM NaCl, 0.2mM MgCl 2 and 25mM, Tris and 50nM fluorescein-labeled cTAR. Then the pH was stabilized at 7.4 by addition of HCl. Five independent tests were carried out so that each of these peptides was added at increasing concentrations in test medium. The binding of these five cTAR peptides was measured by measuring fluorescence at increasing concentrations of peptides. The experiment was carried out for each of the abovementioned peptides according to the same principle as that described in Example 4.

The results obtained are shown in FIG. 5. The more the peptides bind to cTAR, the higher the anisotropy measurement. As for NCp7, the number of binding sites of the above peptides on cTAR is 11. The measured binding constants of the five peptides tested (pA, pB, pC, pD and pE) are shown in Table 3 below.

Table 3: Binding constants (K) of peptides according to the invention with cTAR Peptides K (M-1) pA 70 × 103 pB 130 × 103 pC 200 × 103 pD 60 × 103 pE 800 × 103 These measured affinities are presumably under -stimated with respect to the actual affinities of the peptides according to the invention to the cTAR sequences.

These results show that the peptides according to the invention bind to the cTAR sequences.

EXAMPLE 7 Destabilization of cTAR with Peptides According to the Invention The destabilizing properties of the five abovementioned peptides (pA, pB, pC, pD and pE) were tested on the cTAR sequences obtained in example 2. For this purpose, a test medium was made by mixing in distilled water: 30mM NaCl, 0.2mM MgCl 2 and 25mM, Tris and 100nM labeled cTAR obtained in Example 2. Then the pH was stabilized at 7 The destabilization of cTAR by the peptides was measured at different concentrations of peptides by fluorescence spectroscopy (FIG. 6). Destabilization was described by the change in fluorescence intensity, compared with unlabeled cTARs. When cTAR is not destabilized, that is to say in the absence of peptide, the measured intensity (I / lo) is 1. Under the same conditions, in the presence of NCp7 at an NCp7 / cTAR ratio of 11, the measured intensity is 7. These results demonstrate that the peptides according to the invention have a low destabilizing activity of cTAR compared to that of NCp7 (less than 1%). Thus, the inhibitory activity of the peptides according to the present invention does not go through the destabilization of cTAR, but by a competition with NCp7 as presented hereinafter.

Example 8 Measurement of the Competition Between Peptides According to the Invention and NCp7 for the Connection to cTAR A test medium was made by mixing in distilled water: 30 mM NaCl, 0.2 mM MgCl 2 and 25 mM, Tris and 50nM of labeled cTAR obtained in Example 2. Then the pH was stabilized at 7.4 by addition of HCl. The fluorescence measurements were performed using an SLM 8000 spectrofluorometer (Aminco, Urbana, IL). ) at increasing concentrations of peptide (pE), in the presence or absence of 1.5 pM NCp7, according to the same principle as that presented in Example 4. The results obtained are shown in FIG. found that the titration of the NCp7 / cTAR complex by pE decreases the anisotropy. In addition, the addition of an excess of pE in the presence of the NCp7 / cTAR complex gives the same anisotropy value as when pE is present in excess in the presence of cTAR alone. The anisotropy values of the labeled cTAR bound NCp7 are slightly higher than the marked cTAR bound pE anisotropy because the molecular weight of NCp7 is greater than that of pE (Figure 4). The results presented in Figure 7 show that pE competes with NCp7 to bind to cTAR. This competition can be modeled as in Figure 8.

Example 9 Measurement of Peptide Inhibition of the Destabilization of cTAR by NCp7 A test medium was made by mixing in distilled water: 30mM NaCl, 0.2mM MgCl 2 and 25mM Tris, 33nM cTAR labeled obtained in Example 2 and 660nM of NCp7. Then the pH was stabilized at 7.4 by addition of HCl. The fluorescence measurement was carried out by the fluorescence measurement was carried out using a spectrofluorometer (FluoroLog Horiba, Jobin Yvon, Longjumeau) with concentrations increasing peptides (pA, pB, pC, pD and pE) according to the same principle as that shown in Example 4. A decrease in fluorescence was found (Figure 9) indicating that the peptides of the invention effectively inhibit the destabilization of cTAR induced by NCp7. From Figure 9 it was possible to determine 50% inhibitory concentration values (IC50). This experiment was carried out at different concentrations of cTAR and NCp7 with respect to the peptide pE. The experimental results are shown in Table 4 below: Table 4: 50% inhibitory concentration of pE on the complex cTARINCp7 [cTAR], nM [NCp7], nM IC50, nM IC50 / [NCp7] 33 660 500 0, 76 50 1000 1000 1.00 600 687 1.15 20 200 150 0.75 5 55 64 1.16 These results show that the IC50 is dependent on the concentration of NCp7 and not on the concentration of cTAR, and proves the mechanism Inhibiting the peptides according to the invention on NCp7. In order to compare the effectiveness of the peptides according to the invention, on the inhibition of the destabilization induced by NCp7, the IC50 / [NCp7] ratio was used. For the pE peptide, the IC50 / [NCp7] ratio is about 0.7 to 1, 25 indicating that the NCp7 induced destabilization is reduced by a factor of two when 0.7 to 1 pE is added per cTAR. Since eleven NCp7 molecules bind to cTAR, it has been deduced that a very small amount of pE can greatly reduce the activity of NCp7 (Figure 10). The IC50 / [NCp7] ratio values of five tested peptides (pA, pB, pC, pD and pE) are shown in Table 5 below. Table 5: IC50 / [NCp7] Ratio of peptides Peptides IC 50 / [NCp 7] pA 7 pB 1 pC 1 pD 4 pE 0.7 These data are shown in Figure 12 and are correlated to the binding constants of these peptides. The inhibition is represented by the inverse of the IC50 / [NCp7] ratio and the binding constant by its relative logarithm with respect to the binding constant of pE. This experiment confirms that a partial ejection of NCp7 from cTAR by the peptides according to the invention is sufficient to inhibit the destabilizing activity of NCp7 on cTAR. A schematic representation of the interaction mechanisms between NCp7, cTAR and the peptides according to the invention is shown in FIG. 8.

EXAMPLE 10 Test of the Efficacy of Linear and Cyclic Peptides According to the Present Invention on the Inhibition of the Destabilization of cTAR by NCp7 A test medium was made by mixing in distilled water: 30 mM NaCl, 0, 2mM MgCl2 and 25mM Tris, 0.02pM labeled cTAR obtained in Example 2 and 0.2pM NCp7. Then the pH was stabilized at 7.4 by addition of HCl. Several tests were carried out so that each of the peptides shown in Tables 5, 6, 7 and 8 below was added to medium in concentrations growing. The peptides shown in Table 5 are linear peptides.

Those shown in Table 6 are linear peptides on which a sequence reports SQPKRRKK (SEQ ID NO: 307) has been added (Morris et al [12]). The peptides shown in Table 7 are cyclic peptides whose ring was formed using a spacer arm: CH2-C6H4-CH2. The cyclization was carried out according to the protocol described in Jiang et al. (Jiang, Sheng, Li, Zheng, Ke, Ke; Roller, Peter P., Current Organic Chemistry, 12 (17), 1502-1542 (2008) [33]). The peptides shown in Table 8 are cyclic peptides whose ring was formed by intramolecular cyclization due to the presence of two cysteine residues in the peptide sequence. Cyclization was performed by oxidation of the C- and N-terminal cysteines to 0.1 mg / ml in 0.1% ammonium carbonate solution at 4 ° C for 16h. The oxidation reaction was followed by HPLC / mass spectrometry analysis. After cyclization was complete, TFA (10% in water) was added until a pH of less than 4. The peptides were then lyophilized with acetonitrile (50%, v / v). / v in water) and stored at -20 ° C. The experimental results were obtained by measuring the fluorescence in the same manner as in Example 7 and are illustrated by FIGS. 14A, 14B, 14C and 14D. The results of peptide inhibitory activity at a concentration of 1 μM are shown in Tables 6-9 below, wherein R1 and R2 correspond to the relative fluorescence intensity of the labeled NC / cTAR complexes. These are two independent measurements of each other. R1 and R2 thus correspond to the inhibitory activity calculated from the formula R = If / Ifmax, in which Ifmax corresponds to the measured fluorescence of the cTAR / NCp7 complex and If corresponds to the fluorescence measured in the presence of 1 μM of the peptide. R ,,, is the average of the values R1 and R2.

Table 6: Measurement of the Inhibitory Activity of the Linear Peptides According to the Invention on the Destabilization of cTAR by NCp7 Peptides SEQ ID No. RI ID No. p7 KVKFTARRGKwGRQMKK 151 0.30 0.17 0.23 p28 KKVKCFTARRGWGCRQMKK 78 0.34 0 , 0.32 p1 KVKFTARRGwGRQMKK 152 0.35 0.32 0.33 p2 KVKFTARRGWGRQMKK 153 0.42 0.42 0.42 p9 KVKFTARRGKGwGRQMKK 235 0.50 0.40 0.45 p8 KVKFTARRGKGWGRQMKK 259 0.52 0.40 These results confirm the inhibitory activity of the linear peptides of the present invention. TABLE 7 Measurement of the Inhibitory Activity of the Linear Peptides According to the Invention Linked to a Signal Peptide on the Destabilization of cTAR by NCp7 Peptides SEQ ID No. RI ID No. p11 KVKFTARRGWGRQMKKSQPKRRKK 315 0.13 0.27 0.20 p10 KVKFTARRWGRQMKSQPKRRKK These results show that the addition of the signal peptides and SQPKRRKK (SEQ ID No. 307) to the C-terminus does not interfere with the inhibitory activity of the peptides according to the invention. .

Table 8: Measurement of the inhibitory activity of the cyclic peptides according to the invention on the destabilization of cTAR by NCp7 and whose cycle is transformed via a gold-spacer spacer Peptides SEQ Size RI R2 Rm ID of the cycle No. p14 KKCKFTARRGWCGRQMKK 32 10 0.33 0.25 0.2910 p13 KKVKFCARRGWCRQMKK 68 7 0.21 0.40 0.31 p17 KKVKFCARRGWGCRQMKK 69 8 0.26 0.39 0.32 p15 KKCKFTARRGWGCRQMKK 46 11 0.21 0.43 0.32 p29 KKVKCFTARRGWGCRQMKK 78 10 0.37 0.41 0.39 p19 KKVKFCTARRGWGCRQMKK 82 9 0.58 0.38 0.48 p18 CKKVKFTARRGWGRQMKKC 5 19 0.68 0.34 0.51 p16 KKVKFCTARRGWCRQMKK 81 8 0.69 0.62 0 These results show that cyclic peptides whose ring has been formed using a spacer arm also make it possible to inhibit the destabilization of cTAR by NCp7. Table 9: Measurement of the inhibitory activity of the cyclic peptides according to the invention on the destabilization of cTAR by NCp7 and whose cycle is formed via an intramolecular disulfide bridge Peptides SEQ Size RI R2 Rm ID No. of cycle No. p25 CKKVKFTARRGWGRQMKKC 5 19 0 , 06 0.34 0.20 p22 KKCKFTARRGWGCRQMKK 46 11 0.15 0.28 0.21 p24 KKVKFCARRGWGCRQMKK 69 8 0.20 0.32 0.26 p21 KKCKFTARRGWCGRQMKK 32 10 0.29 0.42 0.35 p26 KKVKFCTARRGWGRQMKK 82 9 0.33 0.60 0.46 p23 KKVKFCTARRGWCRQMKK 81 8 0.45 0.26 0.36 p20 KKVKFCARRGWCRQMKK 68 7 0.48 0.31 0.40 10 These results show that cyclic peptides whose cycle has been formed intramolecular cyclization also makes it possible to inhibit the destabilization of cTAR by NCp7.

No correlation between cycle size and peptide activity was observed. In addition, the insertion of cysteine into the peptides according to the invention and the cyclization of these peptides do not therefore disturb their inhibitory activity. These results show that all the peptides, linear or cyclic, according to the invention make it possible to inhibit the destabilization of cTAR20 by NCp7.5. Furthermore, the peptides whose cyclization has been carried out by an intramolecular disulfide bridge are more effective than the peptides whose cyclization was carried out via the spacer arm.

EXAMPLE 11 Cellular Tests of the Peptides According to the Invention on an Attenuated HIV-1 Strain This experiment was carried out in a laboratory with a L2 safety level. The HIV-1 pNL4-3 DNA, corresponding to the infectious molecular clone, was provided by the National Institute of Health, USA. When a cell is infected with HIV-1 pNL4-3, it expresses a green fluorescent protein called GFP ("Green Fluorescent Protein"). The detection of fluorescence emitted by infected cells was carried out at 504 nm (with excitation at 395 nm) using a Zeiss epifluorescence microscope or a cell sorter (FACS, Excalibur). This allowed to determine the level of infection of these cells. Plasmid pcDNA3.1 (Clonetech, USA) was used as a control DNA vector.

The 293T human cell line, the HeLa P4 cells expressing the CD4 receptor, the LacZ gene under the control of HIV-1 LTR and the HeLa cells used in this protocol were cultured in minimal essential Dulbecco medium (DMEM), supplemented with serum 10% fetal calf and 10U penicillin and 10 μg / ml streptomycin 293T cells were transfected, using the calcium phosphate method (Mangeot PE, Duperrier K, Negro D, Boson B, Rigal D, Cosset FL Darlix JL, Mol Ther. 2002; 5: 283-90). HeLa cells were transfected with the DNA using the Fugene (trademark) transfection method (Invitrogen, USA) to allow immunofluorescence staining.

To analyze the virus production, the cells were washed with PBS and the medium was changed 5h after transfection. One to two days after transfection, supernatants from cultures containing virus particles were harvested and clarified by filtration (0.45 μm, Nalgen). The cells were then washed and lysed with 0.5% Triton-PBS. The virions thus obtained were then purified from the filtered culture supernatants through a pad of 20% sucrose in TNE (100mM NaCl, 10mM Tris HCl, pH 7.4 and 1mM EDTA), obtained after centrifugation at 35,000. rpm for 1 hour in a Beckman centrifuge and SW41 rotor. To measure virus production, a Cap24 ELISA test was performed. Aliquots of viral supernatant (free Cap24 + associated virions = S) of the same volume and pellets of virions obtained by ultracentrifugation (V) were resuspended in a medium comprising 0.5% Triton, and deposited on a 96-well plate. covered with 10 μg / ml of anti-Cap24 antibody (23A5G and 3D10G9B8, BioMerieux, France) and then blocked with 10% horse serum in PBS-0.05% Tween-20. A biotinylated anti-Cap24 secondary antibody (BioMerieux, France) was added. The ELISA test was then revealed with streptavidin and orthophenylenediamine (OPD) -H2O2 (Sigma). The plate was then read on an ELISA plate reader at 490 and 630 nm. Viral infectivity was assessed on HeLaP4 cells according to the protocol described in Grigorov et al. (B Grigorov et al., Retrovirology 2007 [35]).

Hela cells were placed at 8 × 10 4 cells in DMEM medium, supplemented with 10% fetal calf serum and 10 μl of penicillin and 10 μg / ml streptomycin in an atmosphere containing 5% CO2 at 310.15 K (37 μg). At 24 hours, the culture medium was renewed and the peptide p2 (SEQ ID NO: 153) complexed with "NanoVepep" of sequence Ac-ALWRALWFRLWRLAWFRLWR-cysteamide (SEQ ID NO: 312) was added in the medium in concentrations increasing from 25 to 500 nM.

The antiviral activity was determined by measuring the percentage of expression of GFP by Hela cells. This experiment was also carried out with the peptide p10 (SEQ ID No. 316) complexed with "NanoVepep" and p23 (SEQ ID No. 81) complexed with "NanoVepep" at increasing concentrations of 25 to 500 nM, or in the presence of AZT, a nucleoside inhibitor of reverse transcriptase (NRTI), at increasing concentrations of 25 to 500 μM. The experimental results are presented in FIG. 15. All the peptides tested, in accordance with the present invention, have demonstrated remarkable antiviral activity, even at nanomolar concentrations. The p23 cyclic peptide exhibited the most effective inhibitory activity. In particular, at a concentration of 100 nM the p23 peptide was more effective than the AZT reference compound at a concentration of 25 μM. In addition, maximal antiviral activity, i.e., 100% inhibition of GFP production was observed for this p23 peptide when used at a concentration of 500 nM.

EXAMPLE 12 Cellular Tests of the Peptides According to the Invention on a Virulent Virus of HIV-1 These experiments were carried out in the laboratory of high biological safety of the BSL3 type of ENS Lyon, France. In this experiment, the NL4-3 infectious strain was used on SUPT1 lymphocytes, natural targets of the virus. The SUPT1 lymphocytes were infected in the presence of the peptides 3o p2, p10 and p23, under the same conditions and concentrations as those presented in Example 11.

After a night of culture (about 12 hours) the culture medium was replaced to eliminate residual viruses and allow the production of new viruses. The cells were then held for 4 days. The antiviral activity was determined by measuring the percentage of expression of GFP by the SUPT1 lymphocytes. The release of the viruses was evaluated by measuring the activity of the reverse transcriptase in the medium according to the protocol put in place by Tanchou et al. [20] and Berthoux et al. [36]. The experimental results are presented in FIG. 16. This experiment was also carried out using "NanoVepep" (SEQ ID No. 132) without peptide according to the invention. No inhibition of GFP production was observed. "NanoVepep" therefore has no antiviral activity. All peptides tested, according to the present invention, exhibit antiviral activity against NL4-3 virulent strain. These results demonstrate that the peptides according to the invention make it possible to inhibit the production of HIV-1 in the SUPT1 lymphocytes at nanomolar concentrations, whereas under the same conditions, micromolar concentrations are required for the AZT reference compound. The inventors have found through experiments that the antiviral activity of the p23 peptide is greater than 80% at a peptide concentration of 5 nM.

The peptides according to the present invention thus have an anti-HIV activity much higher than that of AZT, a reference compound for the treatment of AIDS, even at nanomolar concentrations.

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2010 Feb 23.

Claims (14)

REVENDICATIONS1. Peptide comprising the sequence XaXbXcXdXe wherein: Xa is selected from the group consisting of KKVKF (SEQ ID NO: 317), KKVKW (SEQ ID NO: 318), KKVKY (SEQ ID NO: 319), KVKW (SEQ ID NO: 320) , KVKY (SEQ ID NO: 321), KVKF (SEQ ID NO: 322), KKF, KKW and KKY; Xb is selected from the group consisting of T, R, TR, RR, ARR, TAR, TARR (SEQ ID NO: 323), TAAR (SEQ ID NO: 324), TARA (SEQ ID NO: 325), TARRA (SEQ ID NO. No. 326), TAARR (SEQ ID NO: 327), TARAR (SEQ ID NO: 328), TAAARR (SEQ ID NO: 329), TARAAR (SEQ ID NO: 330), TARRAA (SEQ ID NO: 331), AATARR (SEQ ID NO: 332) and AATAAR (SEQ ID NO: 333); Xc is selected from the group consisting of GW, GWD, W, AW and AWD; (cl is nothing or selected from the group consisting of GR, AR, A, R and G; Xe is selected from the group consisting of MK, QMK, QMKK (SEQ ID NO: 334), NMK and NMKK (SEQ ID NO: 335); cysteine residues may optionally be inserted into said sequence for its cyclization. 2. Peptide according to claim 1, said peptide being chosen from SEQ ID Nos. 1 to 306 of the attached list of sequences. The peptide according to claim 1, further comprising, at its carboxy terminal end, a signal peptide allowing it to pass through a cell membrane. A peptide according to claim 3, wherein the signal peptide is selected from SQPKRRKK (SEQ ID NO: 307), SKL, KDEL (SEQ ID NO: 308), PPKKKRV (SEQ ID NO: 309), MMSFVALLLVGILFWAWEAEQLTKCEVFQ (SEQ ID NO: 309). ID 310), MLSLRQSIRFFKCSSRYLL (SEQ ID NO: 311), and ALWRALWFRLWRLAWFRLWR (SEQ ID NO: 312). Peptide according to claim 1, said peptide being linear or cyclic. The peptide according to claim 5, wherein said peptide is cyclic, and wherein two cysteine residues are present or have been integrated at a distance permitting cyclization of the peptide, said cysteine residues being linked together via their free -SH moiety or a spacer arm selected from the group consisting of C1-C6 alkyl and a compound selected from the compounds of the formula: CH2-CH2SN1H2CH2CH2-NOOCH2-CH2 (CH) CH2CH2O-CH Embedded image in which n is an integer ranging from 0 to 10, m is an integer ranging from 0 to 10, wherein n is an integer ranging from 0 to 10, m is an integer ranging from 0 to 10 and X is selected from the group consisting of X (CH2) m-oxygen atom, sulfur atom, CH2 group, NH group and NCH3 group. Peptide according to any one of claims 1 to 6 for use as a medicament. The peptide of claim 7 for use as an anti-retroviral drug. The peptide of claim 7 for use as an anti-HIV-1 drug. The peptide according to any one of claims 7 to 9, the medicament further comprising at least one antiretroviral. A peptide according to claim 10, wherein the at least one antiretroviral is selected from the group consisting of AZT, lamivudine, emtricitabine, didanosine, stavudine, abacavir, zalcitabine, tenofovir, racivir, amdoxovir, apricitabine, elvucitabine, efavirenz, nevirapine, etravirine, delavirdine, rilpivrin, tenofovir, fosalvudine, amprenavir, tipranavir, idinavir, saquinavir, fosamprenavir, ritonavir, darunavir, atazanavir, nelfinavir, kaletra, raltegravir, elvitegravir, MK-2048, enfuvirtide, vicriviroc, TNX-355 and bevirimat. The peptide of claim 10 or 11, comprising said peptide and a combination selected from the group consisting of: zidovudine + lamivudine; abacavir + lamivudine; tenofovir + emtricitabine; abacavir + lamivudine; abacavir + lamivudine + zidovudine; tenofovir + emtricitabine + efavirenz.30 Peptide according to any one of claims 1 to 6, wherein said peptide is in injectable form. 14. A process for synthesizing the peptide defined in any one of claims 1 to 6, said method comprising a synthesis step in Boc chemistry and / or Fmoc chemistry.