MXPA97009682A - The treatment of hiv infections and other viral infections using a combined therapy - Google Patents

Abstract

The present invention relates to novel antiviral combinations for the treatment or prevention of viral infections, in particular, HIV. This novel antiviral therapy employs DP-178 or DP-107, inhibitors of viral fusion, in combination with at least one other antiviral therapeutic agent. The combinations of the invention are better than single therapies alone, and in some cases they are synergistic. The use of DP-178 or DP-107 is an ideal therapy to combine with another antiviral, because the novel mechanism that this therapeutic agent blocks in the transmission of HIV and the non-toxicity of the therapy.

Description

THE TREATMENT OF HIV INFECTIONS AND OTHER VIRAL INFECTIONS USING A COMBINED THERAPY. 1. FIELD OF THE INVENTION This is a continuation in part of Series No. 08 / 481,957, filed on June 7, 1995. The present invention relates to the methods of treatment of viral infections, particularly to HIV infection, using a novel combinatorial therapy. The novel combinatorial therapy employs the peptide DP-178, DP-107 or fragments, analogs and / or homologs thereof, and at least one other therapeutic agent. DP-178 is a peptide corresponding to amino acids 638 to 673 of the transmembrane protein (TM) of HIV-LAI gp41. DP-178 includes portions, analogs and homologs of DP-178, all of which exhibit antiviral activity. Antiviral activity includes, but is not limited to, the inhibition of HIV transmission to uninfected CD-4 + cells. In addition, the invention relates to the use of DP-178 and DP-178 fragments and / or analogs or homologs as inhibitors of retroviral transmission, in particular HIV, to uninfected cells, in humans and non-humans. The present invention also relates to the peptide DP-107 antiviral, a peptide corresponding to amino acids 558 to 595 of the transmembrane protein HIV-lu (TM) gp41, which are present in other enveloped viruses. More specifically, the invention relates to the use of DP-107, fragments and / or analogs or homologues in combination with other therapeutic agents to treat viral infections, particularly HIV infection. In addition, the invention comprises novel pharmaceutical compositions containing DP-178 or DP-107 and at least one other therapeutic agent. 2. BACKGROUND OF THE INVENTION 2.1. The Human Immunodeficiency Virus The human immunodeficiency virus (HIV) is a pathogenic retrovirus and the causative agent of acquired immunodeficiency syndrome (AIDS) and related disorders (Barre-Sinossi, F. et al., 1983, Science 220: 868-870; Gallo, R. et al., 1984, Science 224: 550-503). There are at least two different types of HIV: HIV-1 (Barre-Sinossi, F. et al., 1983, Science 220: 868-870, Gallo, R. et al., 1984, Science 224: 500-503) and HIV-2 (Clavel, F. et al., 1986, Science 223: 343-346; Guyader, M. et al., 1987, Nature 326: 662-669). In addition, a large amount of genetic heterogeneity exists within the populations of each of these types. The infection of human CD-4 + T lymphocytes with an HIV virus gives rise to the decrease of the cell type and finally to opportunistic infections, neurological dysfunctions, neoplastic growth and finally death. HIV is a member of the lentivirus family of retroviruses (Teich N. et al., 1984, RNA Tumor Viruses, Weiss, R. et al., Eds., CSH-press, pp. 949-956). Retroviruses are small enveloped viruses that contain a genome of single-stranded, diploid RNA and replicate through a DNA intermediate produced by the virally encoded reverse transcriptase, an RNA-dependent DNA polymerase (Varmus, H., 1988, Science "• 240: 1427-1439.) Other retroviruses include, for example, oncogenic viruses such as human T cell leukemia viruses (HTLV-1, -II, -III), and feline virus leukemia. HIV consists of a viral nucleus, made up of proteins called p24 and pl8.The viral nucleus contains the viral RNA genome and those enzymes necessary for replication events.The gag myristylated protein forms an external viral capsule around the viral core, which is , in turn, surrounded by a membrane-bound lipid envelope from the infected cell membrane.The glycoproteins on the surface of the HIV envelope are synthesized as a single precursor protein of 160 kD that unfolds by a cellular protease during the formation of the viral buds in two glycoproteins, gp41 and gpl20. Gp41 is a transmembrane protein and gpl20 is an extracellular protein that remains non-covalently associated with pg41, possibly in a trimeric or multimeric form (Hammerwskjold, M. and Rekosh, D., 1989, Biochem Biophys, Acta 989: 269-280). HIV targets T-cells of CD-4 + because the surface protein CD-4 acts as the cellular receptor for HIV-1 viruses (Dalgleish, A. et al., 1984, Nature 312: 767-768, Maddon et al., 1986, Cell 47: 333-348). The introduction of the virus into the cells depends on the gpl20 that binds the cellular receptor molecules of the CD-4 +, while the gp41 anchors the glycoprotein complex of the envelope in the viral membrane (McDougal, JS et al., 1986, Science 231; 382-385; Maddon, P.J. et al., 1986, Cell 47: 333-348) and in this way the tropism of HIV for CD-4 + cells is explained. 2. 2. Treatment of HIV HIV infection is pandemic and diseases associated with HIV represent a major global health problem. Although considerable effort has been put into the successful design of effective therapeutics, there is currently no anti-retroviral medicine curative against AIDS. In attempts to develop these drugs, several stages of the viral life cycle have been considered objective for therapeutic intervention (Mitsuya, H. et al., 1991, FASEB J. 5: 2369-2381). The intervention could potentially inhibit the binding of HIV to cell membranes, the reverse transcription of the HIV RNA genome into the DNA or the exit of the virus from the host cell and the infection of new cell targets. Attempts have been made to develop drugs that can inhibit viral entry into cells, the earliest stage of HIV infection. In this case, the little acid on the CD-4 + receptor cell surface for HIV, for example, has been shown that recombinant soluble CD-4 blocks the infectious capacity of HIV by binding to viral particles before they find the CD-4 molecules immersed in cell membranes (Smith, DH et al., 1987, Science 238: 1704-1717) Certain primary HIV-1 isolates are relatively less sensitive to inhibition by recombinant CD-4 (Daar , E. et al., 1990, Ann. Int. Med. 112: 247-253) In addition, clinical trials of recombinant soluble CD-4 have produced inconclusive results (Schooley, R. et al., 1990, Ann. Int. Med. 112: 254-261; Yarchoan, R. et al., 1989, Proc. Vth Int. Conf. On AIDS, p564, MCP 137.) Drugs directed to virally encoded reverse transcriptase, which include analogues of 2 ', 3'-dideoxynucleosides such as ddT, ddl, ddC, and d4T, have been developed and have also been shown to be active against HIV (Mitsuya, H. et al., 1991, Science 249: 1533-1544). Although beneficial, these nucleoside analogs are not curative, probably due to the rapid emergence of drug resistant HIV mutants (Lander, B. et al., 1989, Science 243: 1731-1734). In addition, medications often have toxic side effects such as bone marrow suppression, vomiting and abnormal liver function. The late stages of HIV replication, which includes the viral-specific secondary crucial process of certain viral proteins, have also been suggested as possible targets of the anti-HIV drug. The process in the late stage depends on the activity of the viral protease i and the drugs that have been developed inhibit this protease (Erikson, J., 1990, Science 249: 527-533). The clinical success of these candidate drugs is still in doubt. Attention is also being paid to the development of vaccines for the treatment of HIV infection. HIV-1 envelope proteins (gpl60, gpl20, gp41) have been shown to be the major antigens for anti-VlH antibodies present in AIDS patients (Barin et al., 1985, Science 228: 1094-1096). Until now, these proteins seem to be the most promising candidates to act as antigens for anti-VlH development. For this purpose, some groups have begun to use various portions of gpl60, pgl20 and / or gp41 as immunogenic targets for the host immune systems. See for example, Ivanoff, L. et al., U.S. Pat. No. 5,141,867; Saith, G. et al., WO 92/22, 654; Schaffer an, A., WO 91-09,872; For Bear, C. et al., WO 90 / 07,119. The clinical results related to these candidate vaccines, however, still remain for the future. At present, double-stranded RNAs, which manifest a general immune response, have been used in combination with antivirals such as interferon, AZT and phosphonoformate to treat viral infections, see Carter, W., US Patent No. 4,950,652. In addition, a therapy that combines a nucleoside pyrimidine analog and a uridine phosphorylase inhibitor has been developed for the treatment of HIV, see So adossi, J.P. et al., U.S. Patent 5,077,280. Although these specific therapies may prove to be beneficial, combination therapy generally has the potential for antagonism, as demonstrated in vitro with azidoti idine (AZT) and ribavirin. See U.S. Patent No. 4,950,652. Moreover, combination therapy is potentially problematic due to the high toxicity of most anti-HIV therapeutic agents and their low level of effectiveness. In this way, there is a need for a combination therapy that is effective and non-toxic. The present invention provides novel combination therapy based on the use of viral fusion inhibitors (DP-178 and DP-107, etc.) in combination with other antivirals. DP-178 and DP-107 are both novel therapeutic agents that prevent the virus from fusing with the cell, thereby effectively preventing transmission of the virus from cell to cell. In addition, "DP-178 and DP-107 have been shown to be non-toxic in in vitro and animal studies." The present invention provides the first reported use of these peptides in combination with another antiviral or any other therapeutic agent. 3. SUMMARY OF THE INVENTION The present invention relates to methods of treating or preventing viral infections, in particular HIV infections, in mammals, including humans, by administering an effective amount of DP-178, or a derivative thereof. pharmaceutically acceptable thereof. in combination with at least one other therapeutic agent. The present invention also relates to methods of treating or preventing viral infections, in particular HIV infections, in mammals, including humans, by administering an effective amount of DP-107 or pharmaceutically acceptable derivatives thereof. in combination with at least one other therapeutic agent. More specifically, the invention relates to methods of treating or preventing viral infections in mammals, including humans, by administering an effective amount of DP-107, DP-178 or pharmaceutically acceptable derivatives thereof, in combination with at least another viral agent. The invention includes the administration of the active agents, for example, DP-107, DP-178 or another antiviral concomitantly or in sequence, including cyclic therapy. Cyclic therapy involves the administration of a first antiviral compound for a period of time, followed by the administration of a second antiviral compound for a period of time and the repetition of this sequential administration, ie the cycle, to reduce the development of the resistance to one of the therapies. The invention comprises combinations of DP-107, DP-178 or pharmaceutically acceptable derivatives thereof and at least one other therapeutic agent, particularly another antiviral, which are synergistic, ie, better than any single agent or therapy.

The invention also comprises combinations of DP-178, DP-107 or a pharmaceutically acceptable derivative thereof with at least one other antiviral having a different site of action than the viral fusion inhibitor. This combination provides an improved therapy based on the double action of these therapeutic agents whether the combination is synergistic or additive. The present invention also consists of methods of treatment or prevention of HIV infection in mammals, including humans, by administration of an effective amount of DP-107, DP-178 or a pharmaceutically acceptable derivative thereof in combination with at least one other therapeutic agent, in particular at least one other antiviral. The novel antiviral combinations of the present invention provide a means of treatment that not only reduces the effective dose of any drug necessary for antiviral activity, thereby reducing toxicity, but can also improve the absolute antiviral effect as a result of virus attack by the multiple mechanisms. In the same way, novel antiviral combinations provide a means to eliminate the development of viral resistance to a single therapy, thereby providing the physician with a more effective treatment.

Another aspect of the invention comprises pharmaceutical compositions and formulations for treating or preventing viral infections, in particular HIV infections, wherein the compositions contain an effective amount of DP-178, DP-107, or a pharmaceutically acceptable derivative thereof. these, at least one additional therapeutic agent and a pharmaceutically acceptable carrier. Therapeutic agents which are used in combination with DP-178, DP-107 or a pharmaceutically acceptable derivative thereof comprise a wide variety of known treatments.Preferably, the combinations employ DP-107 or DP-178 in combination with agents with a different mode of attack These agents include, but are not limited to: antivirals such as cytokines, for example, rIFN a, rIFN ß, rIFN;, reverse transcriptase inhibitors, eg, AZT, 3TC, D4T, ddl and other dideoxynucleosides or dideoxyfluoronucleosides, inhibitors of the formation of the cap or cap of viral mRNA, such as ribavirin, inhibitors of HIV protease, such as ABT-538 and MK-639, amphotericin B as a lipid binding molecule with anti-activity. -VlH; and catanospermine as an inhibitor of glycoprotein processing.

Thus, the present invention provides an improved antiviral therapy for the treatment of a broad spectrum of viruses including HIV. The present invention also provides combinatorial therapy that produces improved efficacy over any agent used as a single agent therapy. In addition, the invention provides combinatorial therapy that allows reducing the toxicity of DP-178 and DP-107 and / or the therapeutic agent with which the peptides are used; thereby providing a superior therapeutic index.

The present invention provides a combinatorial therapy that offers a means to eliminate the development of viral resistance to a single therapy. 3. 1. Definitions When used herein the term "viral infection" describes a disease state in which a virus invades healthy cells, the uses of the reproductive machinery of the cell to multiply or replicate and finally the lysis of the cell giving as a result cell death, the release of viral particles and the infection of other cells by the newly produced progeny viruses. Latent infection by certain viruses is also a possible result of viral infection.

When the term "treatment or prevention of viral infections" is used herein, it means inhibiting the replication of the particular virus, inhibiting viral transmission, or preventing the virus from establishing itself as its host, and alleviating or alleviating it. the symptoms of the disease caused by the viral infection. The treatment is considered therapeutic if there is a reduction in viral load, decrease in mortality and / or morbidity. The term "synergistic" when used herein refers to a combination that is more effective than the additive effects of any of two or more individual agents. A synergistic effect, when used herein refers to the ability to use lower amounts (doses) of any individual therapy to treat or prevent viral infection. Lower doses result in lower toxicity without reducing efficacy. In addition, a synergistic effect can give rise to improved efficacy, i.e., better antiviral activity. Finally, synergy can result in better prevention or reduction of viral resistance against any individual therapy. A determination of a synergistic interaction between DP-178 or DP-107, and another therapeutic agent can be based on the results that were obtained from the antiviral assays described in Section 5.5. The results of these tests were analyzed using the Chou and Talalay combination method (Chou and Talalay, 1984, Adv. Enzyme Regul. 22: 27-55) and the 'Dose-Effect Analysis with Microcomputers' program (Chou and Chou, 1987). , software and manual, P19-64, Elsevier Biosoft, Cambridge, UK) to obtain a Combination Index. The values of the Combination index < 1 indicates the synergy, values > 1 indicate antagonism and values equal to 1 indicate additive effects. The results of these tests are also analyzed using the method of Pritchard and Shipman (Pritchar and Shipman, 1990 Antiviral Research 14: 181-206). This computer program by means of the three-dimensional graphic analysis of the results allows a determination of a synergistic or antagonistic interaction between the antiviral agents. The term "pharmaceutically acceptable carrier" refers to a carrier medium that does not interfere with the effectiveness of the biological activity of the active ingredient, is chemically inert and non-toxic to the patient to whom it is administered. When used herein the term "pharmaceutically acceptable derivative" refers to any homologue, analog or fragment corresponding to the peptides DP-178 or DP-107 as described in Section 5.1.2. posterior that presents antiviral activity and is relatively non-toxic to the individual. The term "therapeutic agent" refers to any molecule, compound or treatment, preferably an antiviral, which helps in the treatment of a viral infection or the diseases caused by it. Peptides are defined herein as organic compounds consisting of two or more amino acids covalently linked by peptide bonds. The peptides can be mentioned with respect to the number of '-constituent amino acids, ie, a dipeptide contains two amino acid residues, a tripeptide contains three, etc. Peptides containing 10 or fewer amino acids can be mentioned as oligopeptides, while those with more than 10 amino acid residues are polypeptide. Peptide sequences defined herein are represented by one letter symbols for amino acid residues as follows: A (alanine) R (arginine) N. { asparagine) D (aspartic acid) C (cysteine) Q (glutamine) E (glutamic acid) G (glycine) H (histidine) I (isoleucine) L (leucine) K (lysine) M (methionine) F (phenylalanine P (proline ) S (serine) T (threonine) W (tryptophan) Y (tyrosine) V (valine) 4. BRIEF DESCRIPTION OF THE FIGURES Figure 1. Amino acid sequence of DP-178 (SEQ ID: 1) from HIVIAI; homologues of DP-178 derived from HIV-1SF2 (DP-185; SEQ ID: 3), HIV-1RF (SEQ ID: 4), and HIV-lm (SEQ ID: 5); DP-178 homologs derived from amino acid sequences of two prototypic HIV-2 isolates, namely HIV-2iüd (SEQ ID: 6) and HIV-2"? HZ (SEQ ID: 7); control peptides: DP-180 (SEQ ID: 2), a peptide that incorporates the amino acid residues of DP-178 into a mixed sequence; DP-118 (SEQ ID: 10) unrelated to DP-178, which inhibits HIV-1 cell-free virus infection; DP-125 (SEQ ID: 8), unrelated to DP-178, also previously showed that it inhibits HIV-1 cell-free virus infection (Wild et al., 1992, Proc. Nati. Acad. Sci. USA 89 : 10, 537-10, 541); DP-116 (SEQ ID: 9), unrelated to DP-178 had previously been shown to be negative for inhibition of HIV-1 infection using the cell-free virus infection assay (Wild, et al., 1992, Proc. Nati, Acad. Sci. USA 89: 10,537-10,541). In all the figures the code of the amino acids of a letter is used. Figure 2. Inhibition of virus-free infection of HIV-1 cells by synthetic peptides. The IC50 refers to the concentration of the peptide that inhibits the IT production of infected cells by 50'¿ compared to the untreated control. Control: the level of IT produced by cultures of untreated cells infected with the same concentration of virus as the treated cultures. Figure 3. Inhibition of virus-free infection of HIV-1 and HIV-2 cells by the synthetic peptide DP-178 (SEQ ID: 1). The concentration IC50: of the peptide needed to inhibit the production of IT in 50'¿ compared to the untreated control. Control: concentration of IT produced by cultures of untreated cells infected with the same concentration of virus as the treated cultures.

Figure 4. Cytotoxicity study of DP-178 (SEQ ID: 1) and DP-116 (SEQ ID: 9) on CEM cells. The cell proliferation data are shown. Figure 5A-C. Antiviral data of the peptide from DP-178. The peptides listed therein were obtained from the region surrounding the DP-178 region of the HIV-1 BRU isolate (eg, amino acid residues 615-717 of pg41). In cases where the peptides contained mutations at the DP-178 site, the mutated amino acid residues are shown with dark background. In cases in which the test peptide had an amino and / or carboxy terminal group added or deleted (in addition to the normal amido and acetyl blocking groups found in these peptides, these modifications are indicated) Figure 5A. The immediate right of the name of the test peptide indicates the size of the test peptide and indicates whether the peptide is derived from an amino acid peptide "walks" through the DP-178 region.The second column on the right indicates whether the The test peptide contains a point mutation, while the column to its right indicates whether certain amino acid residues have been added or deleted from the amino acid sequence derived from DP-178. Figure 5B: The column to the immediate right of the peptide name test indicates whether the peptide represents a truncation of DP-178, the next column to the right indicates whether the peptide contains a point mutation and the column to its right a indicates whether the peptide contains the amino acids that have been added or deleted from the DP-178 sequence itself. Figure 5C. The column to the immediate right of the name of the test peptide indicates whether the test peptide contains a point mutilation, while the column to its right indicates whether the amino acid residues have been added or deleted from the DP-1-78 sequence itself .

Figure 6. Antiviral data of the truncated peptide in the region DP-107 and DP-107 gp41. IC50 as defined in Figure 5C and IC50 values were obtained using purified peptides except where marked with an asterisk (*), in which case the IC50 was obtained using a preparation of impure peptides. Figure 7. Antiviral data of the DP-178-like region of simian immunodeficiency virus (SIV) protein TM (fusion). "NT" means the test was not done.

. DETAILED DESCRIPTION OF THE INVENTION The invention relates to methods of treating HIV infection in mammals, including humans, which consists of administering an effective amount of DP-101, DP-178 or a pharmaceutically acceptable derivative thereof and a effective amount of at least one other therapeutic agent. Preferably, the therapeutic agent is another antiviral agent. The present method provides an improved treatment for viral infection, specifically HIV infection. Specifically, the invention provides synergistic combinations for the treatment of HIV infection containing an effective amount of DP-178, DP-107 or pharmaceutically acceptable derivatives thereof and * at least one member of a broad range of available antiviral compounds. for the treatment of viral diseases. DP-178, DP-107 or a pharmaceutically acceptable derivative thereof are preferably used in combination with retroviral inhibitors, viral protease inhibitors, cytokine or cytokine inhibitors or viral fusion inhibitors. The combinations of the present invention are administered to a patient in an amount sufficient to inhibit viral activity, to inhibit viral expression or to inhibit viral transmission. The method of the invention comprises combinatorial therapy in which DP-178, DP-107 and at least one other therapeutic agent are administered concomitantly, for example, as a mixture separately but concurrently or concurrently; or in sequence, including cyclic therapy. Cyclic therapy includes the administration of a first antiviral compound over a period of time, followed by the administration of a second antiviral compound over a period of time and the repetition of this sequential administration, ie the cycle, to reduce the development of the resistance to one of the therapies. The invention also encompasses cyclic therapy consisting of the administration of a first peptide of the present invention, followed by another antiviral, followed by another peptide of the invention, et. So that the inhibitors of the viral fusion DP-107 and DP-178 or derivatives thereof are used in combination with other antivirals. The invention also comprises the use of a combination of the peptides, for example, DP-107 in combination with DP-178. The administration of DP-178, DP-107 or a pharmaceutically acceptable derivative thereof and one or more "in combination" therapeutic agents includes those in which both agents are administered together as a therapeutic mixture, and also methods in which the two agents are administered separately but simultaneously, for example, as through separate intravenous lines in the same individual. The administration "in combination" also includes the separate administration of one of the drugs given first, followed by the second.

Applicants' novel therapy includes the use of peptides that inhibit viral fusion and transmission of the virus from cell to cell in combination with another therapeutic agent. Without being limited in theory, the present invention is based, in part, on the belief that HIV is considered replicating 24 hours a day from the first day of infection. Therefore, it may be beneficial to use an antiviral treatment in different stages of the viral infection. The combinations described here present the first known use of inhibitors of viral fusion, acting in the first stage of viral infection, in combination with antivirals that have different action objectives. The site of action of DP-178 and DP-107 is on the surface of the virus, preventing the free virus from infecting the host cells and the transmission of the virus from cell to cell. Therefore, without being limited to the theory, applicants consider that DP-178 or DP-107 used in combination with one or more drugs having different targets or mechanisms of action provides an additive or synergistic effect. The combinations of the present invention are advantageous because the drugs that are used will be used in lower and less toxic concentrations. The combination therapy can not only reduce the effective dose of the medication necessary for viral activity, thereby reducing its toxicity, but can also improve the absolute antiviral effect as a result of attack to the virus by multiple mechanisms. Finally, the combinations of the present invention also provide a means to eliminate or diminish the opportunity for development of viral resistance. Preferred treatments that are used in combination with DP-178 and / or DP-107 include, but are not limited to, 5 different attack modes on viruses: inhibition of reverse transcriptase, inhibition of the viral mRNA capsule, inhibition of HIV protease, inhibition of protein glycosylation and inhibition of viral fusion. Agents employing these modes of attack include, but are not limited to, antivirals such as cytokines, for example, rIFN a, rIFN ß, rIFN?; reverse transcriptase inhibitors, for example, AZT, 3TC, D4T, ddl and dideoxyfluoronucleosides, inhibitors of hat formation of viral mRNA, such as ribavirin; HIV protease inhibitors, such as ABT-538 and MK-639; amphotericin B as a lipid-binding molecule with anti-HIV activity; and castanospermine as an inhibitor of glycoprotein processes. . 1. Treatment of HIV with DP-178 or DP-107 5.1.1 Peptides DP-178 and DP-107 DP-178 and DP-107 are peptides that have potent antiviral activity inhibiting the fusion of viruses. These peptides include DP-178, a peptide of 36 amino acids from gp41, fragments and / or analogs of DP-178 and peptides homologous to DP-178. In addition, these peptides can include peptides having antiviral activity that are analogous to DP-107, a peptide of 38 amino acids corresponding to residues 558 to 595 of the transmembrane gp * 41 protein HIV-ILA? and that are present in other viral proteins covered. The use of the peptides of the invention as inhibitors of non-human and human and retroviral. [Sic], especially the transmission of HIV are detailed herein and in the application of US Pat. No. 08 / 073,028, filed 7. June 1993, the application of United States Patent Series No. 08 / 264,531, filed June 23, 1994, the application of United States Patent Series No. 08 / 255,208 filed on June 7, 1994, the application of the US Patent Series No. 08 / 360,107, filed December 20, 1994, US Patent Application Serial No. 08 / 374,666, filed January 27, 1995, US Patent Application Serial No. 08 / 470,896 , filed June 6, 1995, and US Patent Application Serial No. 08 / 485,264, filed June 7, 1995, which are incorporated herein by reference in their entirety. Although not limited to any theory of operation, the following model is proposed to explain the potent anti-HIV activity of DP-178. In the viral protein, gp41, DP-178 corresponds to a putative helix region located at the end of a C terminal of the inio ectod of gp41 and seems to associate with a distal site on gp41 whose interactive structure is influenced by the motif of the leucine zipper, a coiled coil structure, known as DP-107. The association of these two domains can manifest a molecular bond or "molecular brooch" intimately included in the fusion process. It may be that the zipper form of leucine is involved in the membrane fusion while the a-terminal helix form serves as a molecular safety mechanism to regulate the availability of the leucine zipper during fusion. of membrane induced by the virus. When synthesized as peptides, DP-107 and DP-178 are potent inhibitors of HIV infection and fusion, probably by virtue of their ability to form complexes with viral gp41 and interfere with their fusogenic process; for example, during the structural transition of the viral protein from the native structure to the fusogenic state, the DP-107 and DP-178 peptides can access their respective binding sites on the viral gp41, and exert a disruptive or disruptive influence. . A truncated recombinant gp41 protein corresponding to the inio ectod of gp41 containing domains of DP-107 and DP-178 (excluding the fusion peptide, the transmembrane region and the cytoplasmic domain of gp41) did not inhibit HIV-1 induced fusion. . However, when a single mutation was introduced to break the coiled-coil structure of the DP-107 domain-a mutation that gave rise to a total loss of the biological activity of the DP-107 peptides-the inactive recombinant protein became an inhibitor. active of fusion induced by HIV-l. This transformation can result from the release of the powerful DP-178 domain from a molecular zipper with the leucine zipper, the DP-107 domain. The DP-178 peptide of the invention corresponds to amino acid residues 638 to 673 of the transmembrane gp41 protein from the HIV-IAI isolate, and has the sequence of 36 amino acids (reading from amino to terminal carboxy): NH-YTSLIHSLIEESQNQQEKNEQELLELDKWASLWNWF- COOH (SEQ ID: 1) DP-178 also described in co-pending US Patent Applications Series No. 08/470, 896, filed on June 6, 1995, Series No.B 08 / 374,666 filed on January 27, 1995, Series No. 08 / 264,531, filed on June 23, 1994, and Series No. 08 / 255,208, filed on June 7, 1994, which are incorporated herein by reference in their entirety. In addition to the full-length 36-mer DP-178 (ID SEQ: 1), the peptides of the invention can include truncations of the peptide DP-178 (SEQ ID: 1) that exhibit antiviral activity. These truncated peptides DP-178 (ID SEQ: 1) may consist of peptides of between 3 and 36 * • amino acid residues (ie, peptides in size range from 1 tripeptide to a 36-mer polypeptide, and may include, but not it is limited to those listed in Tables I and II below.The peptide sequences in these tables are listed from the amino (left) to the terminal carboxy (right). "X" can represent an amino group (-NH) and "Z" may represent a carboxyl group (-COOH). Otherwise, as described below, "X" and / or "Z" may represent a hydrophobic group, an acetyl group, an FMOG group, an amido group or a covalently linked macromolecule DP-107 is a 38 amino acid peptide corresponding to residues 558 to 595 of the transmembrane (TM) gp41 protein HIV-ILM, which has potent antiviral activity. antiviral peptide from HIV-1 and can also be found in other enveloped viruses ura, different from HIV-l. DP-107 is described in more detail in the co-pending US Patent Applications of Applicants Series No. 08 / 470,896, filed June 6, 1995, Series No. 08 / 374,666, filed January 27, 1995, Series No. 08 / 264,531, filed on June 23, 1994, and Series No. 08 / 255,208, filed on June 7, 1994, which are incorporated herein by reference in their entirety. Removals of the truncations of DP-107 or "DP-178 are also within the scope of the invention." These deletions consist of the removal of one or more amino acids from DP-107 or DP-107- [sic] as a sequence of peptides, with the lower limit length of the resulting peptide sequence being from 4 to 6 amino acids These deletions may include a single small contiguous portion or more than one of the peptide sequences One or more of these deletions may be introduced in DP -107 or DP-107 truncations, as long as these deletions result in peptides that can still be recognized by the search motifs 107x178x4, ALLMOTI5 or PLZIP described herein, or may otherwise exhibit antifusogenic or antiviral activity , or present the ability to modulate the intracellular processes that include the structures of coiled coil peptides.

TABLE I CARBOXI TRUNCATIONS IN DP-178 (SEQ ID: 1) X-YTS-Z X-YTSL-Z X-YTSLI-Z X-YTSLIH-Z X-YTSLIHS-Z X-YTSLIHSL-Z X-YTSLIHSLI-Z X -YTSLIHSLIE-Z X-YTSLIHSLIEE-Z X-YTSLIHSLIEES-Z X-YTSLIHSLIEESQ-Z X-YTSLIHSLIEESQN-Z X-YTSLIHSLIEESQNQ-Z X-YTSLIHSLIEESQNQQ-Z X-YTSLIHSLIEESQNQQE-Z X-YTSLIHSLIEESQNQQEK-Z X-YTSLIHSLIEESQNQQEKN-Z X -YTSLIHSLIEESQNQQEKNE X-Z-X-Z YTSLIHSLIEESQNQQEKNEQ YTSLIHSLIEESQNQQEKNEQE-Z-X-Z-X-YTSLIHSLIEESQNQQEKNEQEL YTSLIHSLIEESQNQQEKNEQELL X-Z-X-Z YTSLIHSLIEESQNQQEKNEQELLE YTSLIHSLIEESQNQQEKNEQELLEL-Z-X-Z-X-YTSLIHSLIEESQNQQEKNEQELLELD YTSLIHSLIEESQNQQEKNEQELLELDK X-Z-X-Z YTSLIHSLIEESQNQQEKNEQELLELDKW -YTSLIHSLIEESQNQQEKNEQELLELDKWA X-Z-X-Z YTSLIHSLIEESQNQQEKNEQELLELDKWAS YTSLIHSLIEESQNQQEKNEQELLELDKWASL-Z-X-Z-X-YTSLIHSLIEESQNQQEKNEQELLELDKWASLW YTSLIHSLIEESQNQQEKNEQELLELDKWASLWN-Z X-Z-X-YTSLIHSLIEESQNQQEKNEQELLELDKWASLWNW YTSLIHSLIEESQNQQEKNEQELLELDKWASLWNWF-Z The one letter amino acid code is used. In addition, "X" may represent an amino group, a hydrophobic group, including but not limited to carbobenzoxyl, dansyl, or t-butyloxycarbonyl; an acetyl group; a group 9-fluorenylmethoxycarbonyl (FMOC); a macromolecular carrier group including, but not limited to conjugates of fatty acids-lipids, polyethylene glycol or carbohydrates. "Z" may represent a carboxyl group; an amino group; a t-butyloxycarbonyl group; a macromolecular carrier group including, but not limited to conjugates of fatty acids-lipids, polyethylene glycol or carbohydrates.

TABLE II AMINO TRUNCINGS ON DP-178 (ID SEQ; 1) X-NWF-Z X-WNWF-Z X-LWNWF-Z X-SLWNWF-Z X-ASLWNWF-Z X-WASLWNWF-Z X-KWASLWNWF-Z X -DKWASLWNWF-Z X-LDKWASLWNWF-Z X-ELDKWASLWNWF-Z X-LELDKWASLWNWF-Z X-LLELDKWASLWNWF-Z X-ELLELDKWASLWNWF-Z X-QELLELDKWASLWNWF-Z X-EgELLELDKWASLWNWF-Z X-NEQELLELDKWASLWNWF-Z X-KNEQELLELDKWASLWNWF-Z X -EKNEQELLELDKWASLWNWF Z-X-Z-X-QEKNEQELLELDKWASLWNWF QQEKNEQELLELDKWASLWNWF X-Z-X-Z NQQEKNEQELLELDKWASLWNWF QNQQEKNEQELLELDKWASLWNWF-Z-X-Z-X-SQNQQEKNEQELLELDKWASLWNWF ESQNQQEKNEQELLELDKWASLWNWF Z-X-Z-X-EESQNQQEKNEQELLELDKWASLWNWF 1EESQNQQEKNEQELLELDKWASLWN FZ X-Z-X- LIEESQNQQEKNEQELLELDKWASLWNWF SLIEESQNQQEKNEQELLELDKWASLWNWF Z-X-Z-X-HSLIEESQNQQEKNEQELLELDKWASLWNWF IHSLIEESQNQQEKNEQELLELDKWASLWNWF LIHSLIEESQNQQEKNEQELLELDKWASLWNWF-Z X-Z-X-Z-X-SLIHSLIEESQNQQEKNEQELLELDKWASLWNWF TSLIHSLIEESQNQQEKNEQELLELDKWASLWNWF-Z X-YTSLIHSLIEESQNQQEKNEQELLELDKWASLWNWF-Z The one-letter amino acid code is used. In addition, "X" may represent an amino group, a hydrophobic group, including but not limited to carbobenzoxyl, dansyl, or t-butyloxycarbonyl; an acetyl group; a 9-fluorenylmethoxycarbonyl group (FMOC); a macromolecular carrier group including, but not limited to conjugates of fatty acids-lipids, polyethylene glycol or carbohydrates. "Z" may represent a carboxyl group; an amino group; a t-butyloxycarbonyl group; a macromolecular carrier group including, but not limited to conjugates of fatty acids-lipids, polyethylene glycol or carbohydrates. . 1.2. Analogues and Homologs of DP-178 and DP-107 The antiviral peptides of the invention also include DP-178 analogs and / or truncations of DP-178 which may include, but are not limited to, peptides consisting of the DP- sequence. 178 (SEQ ID: 1) or truncated sequence DP-178, which contains one or more amino acid substitutions, insertions and / or deletions. Analogs of DP-178 homologs, which are described below, are also within the scope of the invention. The DP-178 analogs of the invention exhibit antiviral activity and may, in addition, possess additional advantageous characteristics, for example, increased bioavailability and / or stability, or reduced host immune recognition.

The envelope proteins of HIV-1 and HIV-2 are structurally different, but there is an evident conservation of the amino acids within the regions corresponding to DP-178 of HIV-1 and HIV-2. The conservation of amino acids is of a periodic nature, which suggests something about the conservation of the structure and / or function. Thus, a possible class of amino acid substitutions would include those amino acid changes that are predicted to stabilize the structure of the DP-178 peptides of the invention. The amino acid substitutions may be of a conserved or non-conserved nature. Conserved amino acid substitutions consist of replacing one or more amino acids of the DP-178 peptide sequence (SEQ ID: 1) with amino acids of charge, size and / or similar hydrophobicity characteristics, such as, for example, an amino acid substitution of the amino acid. glutamic acid (E) in aspartic acid (D). When only conserved substitutions are made, the resulting peptide is functionally equivalent to DP-178 (SEQ ID: 1) or DP-178 peptide from which it is derived. Non-conserved substitutions consist of replacing one or more amino acids of the peptide sequence of DP-178 (SEQ ID: 1) with amino acids having unsymmetrical charge, size and / or hydrophobicity characteristics, such as, for example, a substitution of glutamic acid (E) by valine (V). The amino acid insertions may consist of individual amino acid residues or residue elongations in the range from 2 to 15 amino acids in length. One or more insertions can be introduced into DP-178 (SEQ ID: 1), DP-178 fragments, analogs and / or DP-178 homologs. Deletions of DP-178 (SEQ ID: 1), DP-178 fragments, analogs and / or DP-178 homologs are also within the scope of the invention. These deletions consist of the removal of one or more amino acids from DP-178 or the sequence of DP-178-like peptides, with the length at the lower limit of the resulting peptide sequence from 4 to six amino acids. These deletions may include a single contiguous small portion or more than one of the peptide sequences. The peptides of the invention may further include homologues of DP-178 (SEQ ID: 1) and / or truncations of DP-178 having antiviral activity. These DP-178 homologs are peptides whose amino acid sequences are composed of the amino acid sequences of peptide regions of other (ie, different HIV-ILAI) viruses that correspond to the peptide region of gp41. which comes from DP-178 (SEQ ID: 1). These viruses may include, but are not limited to, other HIV-1 isolates and HIV-2 isolates. DP-178 homologues from the corresponding gp41 peptide region of others (ie, do not give HIV-IIAI) isolated from HIV-1 may include, for example, peptide sequences as shown below. NH2-YTNTIYTLLEESQNQQEKNEQELLELDKWASLWNWF-COOH (DP-185; ID SEQ: 3); NH2-YTGI IYNLLEESQNQQEKNEQELLELDKWANLWNWF-COOH (SEQ ID: 4); NH2-YTSLIYSLLEKSQIQQEKNEQELLELDKWASLWNWF-C00H (SEQ ID: 5); SEQ ID: 3 (DP-185), SEQ ID: 4, and SEQ ID: 5 are derived from isolates of HIV-1SF2, HIV-1RF and HIV-IMN / respectively. The underlined amino acid residues refer to those residues that differ from the corresponding position in the peptide DP-178 (SEQ ID: 1). A homolog of DP-178, DP-185 (ID? EQ: 3), is described in the working example presented in Section 6 below, where it is shown that DP-185 (SEQ ID: 3) presents antiviral activity. The DP-178 homologs of the invention may also include truncations, substitutions, insertions and / or amino acid deletions as described above. In addition, remarkable similarities, as shown in Figure 1, exist within the regions of the HIV-1 and HIV-2 isolates that correspond to the sequence of DP-178. A homologue of DP-178 from the isolate of HIV-2NIHZ has the sequence of 36 amino acids (reading from amino to carboxy terminal): NH2-LEANISQSLEQAQIQQEKNMYELQKLNSWDVFTNWL-COOH (SEQ ID: 7) Table III and Table IV show some truncations potential of the homolog of DP-178 of IH-2NiH2 which may contain peptides of between 3 and 36 amino acid residues (ie, peptides in the size range from a tripeptide to a 36-mer polypeptide). The peptide sequences in these tables are listed from amino (left) to terminal carboxy (right). "X" may represent an amino group (-NH and "Z" may represent a carboxyl group (-COOH). Otherwise, as described below, "X" and / or "Z" may represent a hydrophobic group, an acetyl group, an FMOC group, an amido group or a macromolecule covalently linked as described below.

TABLE III Carboxy Truncations of Homolog DP-178 of HIV-2NIHZ X-LEA-Z X-LEAN-Z X-LEANI-Z X-LEANIS-Z X-LEANISQ-Z X-LEANISQS-Z X-LEANISQSL-Z X- LEANISQSLE-Z X-LEANISQSLEQ-Z X-LEANISQSLEQA-Z X-LEANISQSLEQAQ-Z X-LEANISQSLEQAQI-Z X-LEANISQSLEQAQIQ-Z X-LEANISQSLEQAQIQQ-Z X-LEANISQSLEQAQIQQE-Z X-LEANISQSLEQAQIQQEK-Z X-LEANISQSLEQAQIQQEKN-Z X- LEANISQSLEQAQIQQEKNM X-Z-X-Z LEANISQSLEQAQIQQEKNMY LEANISQSLEQAQIQQEKNMYE-Z-X-Z-X-LEANISQSLEQAQIQQEKNMYEL LEANISQSLEQAQIQQEKNMYELQ X-Z-X-Z LEANISQSLEQAQIQQEKNMYELQK LEANISQSLEQAQIQQEKNMYELQKL-Z-X-Z-X-LEANISQSLEQAQIQQEKNMYELQKLN LEANISQSLEQAQIQQEKNMYELQKLNS Z-X-Z-X- LEANISQSLEQAQIQQEKNMYELQKLNSW LEANISQSLEQAQIQQEKNMYELQKLNSWD X-Z-X-Z LEANISQSLEQAQIQQEKNMYELQKLNSWDV LEANISQSLEQAQIQQEKNMYELQKLNSWDVF-Z-X-Z-X-LEANISQSLEQAQIQQEKNMYELQKLNSWDVFT LEANISQSLEQAQIQQEKNMYELQKLNSWDVFTN Z-X-Z-X-LEANISQSLEQAQIQQEKNMYELQKLNSWDVFTNW LEANISQSLEQAQIQQEKNMYELQKLNSWDVFTNWL-Z The one-letter amino acid code is used. In addition, "X" may represent an amino group, a hydrophobic group, including but not limited to carbobenzoxyl, dansyl, or t-butyloxycarbonyl; an acetyl group; a 9-fluorenylmethoxycarbonyl group (FMOC); a macromolecular carrier group including, but not limited to conjugates of fatty acids-lipids, polyethylene glycol or carbohydrates.

"Z" may represent a carboxyl group; an amino group; a t-butyloxycarbonyl group; a macromolecular carrier group including, but not limited to conjugates of fatty acids-lipids, polyethylene glycol or carbohydrates.

TABLE IV Amino truncations of homolog DP-178 of HIV-2N? Hz X-'N LZ X-TNWL-Z X-FTNWL-Z X-VFTNWL-Z X-DVFTNWL-Z X-WDVFTNWL-Z X-SWDVFTNWL-Z X-Z-X-NSWDVFTNWL LNSWDVFTNWL Z-X-Z-X-KLNSWDVFTNWL QKLNSWDVFTNWL-Z -LQKLNS DVFTNWL-Z X-Z-X-ELQKLNSWDVFTNWL YELQKLNSWDVFTNWL X-Z-X-Z MYELQKLNSWDVFTNWL NMYELQKLNSWDVFTNWL-Z-X-Z-KNMYELQKLNSWDVFTNWL X-EKNMYELQKLNSWDVFTNWL-Z X-QEKNMYELQKLNS DVFTNWL-Z X-QQEKNMYELQKLNSWDVFTN LZ X-IQQEKNMYELQKLNSWDVFTNWL-Z X-QIQQEKNMYELQKLNSWDVFTNWL-Z X-AQIQQEKNMYELQKLNSWDVFTNWL-Z X-QAQIQQEKNMYELQKLNS DVFTNWL-Z X-EQAQIQQEKNMYELQKLNSWDVFTNWL-Z X-LEQAQIQQEKNMYELQKLNSWDVFTN LZ X-SLEQAQIQQEKNMYELQKLNSWDVFTNWL-Z X-Z-X-QSLEQAQIQQEKNMYELQKLNSWDVFTNWL SQSLEQAQIQQEKNMYELQKLNSWDVFTNWL X-Z-X-NISQSLEQAQIQQEKNMYELQKLNSWDVFTNWL ISQSLEQAQIQQEKNMYELQKLNSWDVFTN LZ X-Z-X-Z ANISQSLEQAQIQQEKNMYELQKLNSWDVFTNWL EANISQSLEQAQIQQEKNMYELQKLNSWDVFTNWL-Z-X-Z-LEANISQSLEQAQIQQEKNMYELQKLNSWDVFTNWL The one-letter amino acid code is used. In addition, "X" may represent an amino group, a hydrophobic group, including but not limited to carbobenzoxyl, dansyl, or t-butyloxycarbonyl; an acetyl group; a 9-fluorenylmethoxycarbonyl group (FMOC); a macromolecular carrier group including, but not limited to conjugates of fatty acids-lipids, polyethylene glycol or carbohydrates.

"Z" may represent a carboxyl group; an amino group; a t-butyloxycarbonyl group; a macromolecular carrier group including, but not limited to conjugates of fatty acids-lipids, polyethylene glycol or carbohydrates. . 1.3. Preparation of DP-178 and DP-107 The peptides of the invention can be synthesized or prepared by techniques well known in the art. See, for example, Creiton, 1983, Proteins: Structures and Molecular Principies, W.H. Freeman and Co., NY, which are incorporated herein, as a reference in their completeness. Short peptides, for example, can be synthesized on a solid support or in solution. Longer peptides can make use of recombinant DNA techniques. In this case, the nucleotide sequences encoding the peptides of the invention can be synthesized and / or cloned, and expressed according to techniques well known to those skilled in the art. See, for example, Sambrook et al., 1989, Molecular Cloning, A Laboratory Manual, Vols. 1-3, Cold? Pring Harbor Press, NY. The peptides of the invention may, otherwise, be synthesized so that one or more of the bonds that bind the amino acid residues of the peptides are non-peptide bonds. These alternative non-peptidic linkages can be formed using reactions well known to those skilled in the art and can include, but are not limited to, imino, ester, hydrazide, semicarbazide and azo linkages, to name but a few. In still another embodiment of the invention, the peptides containing sequences described above can be synthesized with additional chemical groups present in their terminal amino and / or carboxy, so that, for example, stability, bioavailability and / or stability are improved. inhibitory activity of peptides. For example, hydrophobic groups, such as the carbobenzoxyl, dancilo or t-butyloxycarbonyl groups, can be added to the terminal amino groups of the peptides. In the same way, an acetyl group or a 9-fluorenyl ethoxycarbonyl group can be placed in the terminal amino acids of the peptides. (see "X" in Tables I to IV above.) In addition, the hydrophobic group, t-butyloxycarbonyl, or an amido group can be added to the carboxy termini of the peptides. (see "Z" in Tables I to IV above.) In addition, the peptides of the invention can be synthesized in a manner that modifies their steric configuration. For example, the D-isomer of one or more of the amino acid residues of the peptides can be used in place of the customary L-isomer. Still further, at least one of the amino acid residues of the peptides of the invention can be substituted by one of the well-known amino acid residues that are not found in nature. Modifications such as these may serve to increase the stability, bioavailability and / or inhibitory action of the peptides of the invention. Any of the peptides described above may, in addition, have a non-peptide macromolecular carrier group covalently attached to their amino and / or carboxy termini. These macromolecular carrier groups can include, for example, conjugates of fatty acids-lipids, polyethylene glycol or carbohydrates. The truncations, analogs and homologs of DP-178 and DP-107 are fully described in the co-pending applications of the applicant series number 08 / 073,028, filed on June 7, 1993, Series Number 08 / 264,531, filed on June 23, 1994 , Series Number 08 / 255,208, filed on June 7, 1994 and Series Number 08 / 360,107, filed on December 20, 1994, which are incorporated herein by reference in their entirety. . 1.4. Therapeutic Uses of the Peptides of the Invention The peptides DP-178 (SEQ ID: 1) of the invention and the fragments, analogs and homologs of DP-178 exhibit potent antiviral activity. The peptides similar to DP-107 and DP-178 of the invention preferably have antiviral activity. As such, the peptides can be used as inhibitors of viral and retroviral transmission to humans and non-humans, especially HIV, to uninfected cells. Human retroviruses whose transmission can be inhibited by the peptides of the invention include, but are not limited to all strains of HIV-1 and HIV-2 and human T lymphocyte viruses (HTLV-1 and II). Non-human retroviruses whose transmission can be inhibited by the peptides of the invention include, but are not limited to, bovine leukosis virus, feline sarcoma and leukemia virus, immunodeficiency virus, sarcoma and simian leukemia and bovine pneumonia virus. Non-retroviral viruses whose transmission can be inhibited by the peptides of the invention include, but are not limited to human respiratory syncytia virus, canine distemper virus (distemper), Newcastle disease virus, human parainfluenza virus and influenza virus. . The invention also comprises the treatment of retroviral and non retroviral viruses . 2. Antivirals that can be used in combination with J2P_-178 or DP l07.

According to the present invention, DP-178 or DP-107, a virus fusion inhibitor, can be used in combination with other therapeutic agents to improve its obtained antiviral effect. Preferably, DP-178 or DP-107 are used in combination with another antiviral agent. These additional antiviral agents that can be used with DP-178 or DP-107 include, but are not limited to those that function on a different target molecule involved in viral replication, e.g., reverse transcriptase inhibitors, protease inhibitors. viral, glycosylation inhibitors; those that act on a different target molecule involved in viral transmission; those that act on a different locus of the same molecule; and those that prevent or reduce the onset of viral resistance. Those skilled in the art will know a wide variety of antiviral therapies that exhibit the aforementioned modes of activity. DP-178 or DP-107 or a pharmaceutically acceptable derivative thereof can also be used in combination with inhibitors of retroviruses, such as nucleoside derivatives. The nucleoside derivatives are modified forms of purine and pyrimidine nucleosides which are the building blocks of RNA and DNA. A large number of the nucleoside derivatives under study as potential anti-HIV drugs give rise to the premature termination of viral DNA replication before the entire genome is transcribed. These derivatives lack the 3 'substituents that can bind to the subsequent nucleosides and result in chain termination. Nucleoside derivatives such as 3'-acid-3'-thymidine (AZT) and dideoxyinosine (ddl) have been exploited as inhibitors of HIV-1 replication, both in vitro and in vivo. Nucleoside analogs are currently the only therapeutic agents allowed for the treatment of HIV infection and AIDS (Fischl et al, 1987 N. Engl. J. Med. 317, 185-191; Mitsuya and Broder, 1987 Nature 325, 773-778). This class of taxa works by inhibiting the reverse transcriptase, causing a block in the synthesis of AüNc (Mitsuya and Broder, 1987), these inhibitors work in the early stage in the infectious cycle of HIV-1 and inhibit the integration into the genome of T cells. However, therapy with AZT gives rise to the development of resistant HIV strains (Larder 1989, 1991, Ibid.) and demonstrates toxicity in patients with AIDS in long-term therapies. (Fischl et al., 1987, N. Engl. J. Med. 317: 185-191; Creagh-Kirk, et al., 1988, J.A.M.A. 260: 3045-3048). In addition, DP-178 or DP-107 or a pharmaceutically acceptable derivative thereof can be used in combination with nucleoside derivatives including but not limited to 2 ', 3' -dideoxydenosine (ddA); 2 ', 3'-dide = oxyguanosine (ddG); 2 ', 3' -dideoxyinosine (ddI); 2 ', 3' - dideoxycytidine (ddC); 2 ', 3' -dideoxythymidine (ddT); 2 ', 3'-dideoxy-dideoxythymidine (d4T) and 3' -acid-2 ', 3'-dideoxythymidine (AZT). Otherwise, the halogenated nucleoside derivatives may be used, preferably the 2 ', 3' -dideoxy-2'-fluoronucleosides including, but not limited to, 2 ', 3'-dideoxy-2' -fluoroadenosine; 2 ', 3'-dideoxy-2'-fluoroinosine; 2 ', 3' -dideoxy-2 '-fluorothymidine; 2 ', 3' -dideoxy-2 '-fluorocytocin; and 2 ', 3'-dideoxy-2', 3 '-didehydro-2' -fluoronucléosides including, but not limited to 2 ', 3' -didehydro-2 '-fluorothymidine (Fd4T). Preferably, the 2 ', 3' -dideoxy-2 '-fluoronucleosides of the invention are those in which the fluoro bond is in the beta configuration, which includes, but is not limited to 2', 3 '-dideoxy-2 '-beta-fluoroadenosine (F-ddA), 2', 3 '-dideoxy-2' -beta-fluoroinosine (Fddl), and 2 ', 3' -dideoxy-2 '-beta-fluorocytocin (F-ddC). These combinations allow one to use a lower dose of the nucleoside derivative thereby reducing the toxisity associated with this agent, without loss of antiviral activity caused by the use of antiviral peptides. Moreover, this combination reduces or prevents viral resistance.

Preferred combinations of the antiviral nucleoside peptides and derivatives within the scope of the present invention include an effective amount of DP-107, DP-178 or a pharmaceutically acceptable derivative thereof and an effective amount of AZT to treat the infection of HIV; and an effective amount of DP-107, DP-178 or a pharmaceutically acceptable derivative thereof and an effective amount of ddI. In accordance with the present invention, DP-178 or DP-107 or a pharmaceutically acceptable derivative thereof may also be used in combination with inhibitors of uridine phosphorylase, which includes, but is not limited to aciclouridine compounds, including benzylacyluridine ( BAU); benzyloxybenzylacyluridine (BBAU); aminomethyl-benzylacyluridine (AMBAU); aminomethyl-benzyloxybenzylaciclouridine (AMB-BAU); hydroxymethyl-benzylacyluridine (HMBAU); and hydroxyethylbenzyloxybenzylalylouridine (HMBBAU). In accordance with the present invention, DP-178 or DP-107 or a pharmaceutically acceptable derivative thereof can also be used in combination with cytokines or cytokine inhibitors, which includes, but is not limited to rIFN a, rIFN ß, rIFN?, TNFa inhibitors, and MNX-160. The rIFN a, (> 108 Ul / mg) and rIFN? (1.4 x 108 IU / mg) human can be obtained from Hoffman LaRoche. The rIFN ß Ser 17 human (1.0 x 108 IU / mg) are obtained from Triton Biosciences. The reference standards are obtained in the Organization World Health Organization (human IFNa WHO B standard, 69, 19 and human IFN ß, WHO No. G-023-902-527 or at the National Institute for Allergic and Infectious Diseases (? Human, National Institute of Health G-023-901-530.) In accordance with the present invention, DP-178 or DP-107 or a pharmaceutically acceptable derivative thereof can be used in combination with viral protease inhibitors, including, but is not limited to, MK-639 (Merck), Invirasa (saquinavir, Roche), ABT-538 (Abbott, CAS Reg. No. 155213-67-5), AG1343, VX0478 (Burroughs Wellcome / Glaxo, CAS Reg. No. 161814-49-9) DMP850 (illegible), SC-52151 (Telinavir). In general, protease inhibitors are considered to function primarily during or after assembly (i.e., the formation of viral buds) to inhibit the maturation of virions to a mature infectious state. For example, ABT538 has been shown to have potent antiviral activity in vitro and favorable pharmacokinetic and safety profiles in vivo (Ho, et al., 1995, Nature 373: 123-126). The administration of ABT-538 in patients with AIDS gives rise to levels of HIV-1 in plasma that decrease exponentially and CD4 lymphocyte counts. increases substantially. The exponential disintegration in the pyramidal viraemia followed by the treatment of ABT-538 manifests both the clearance of the free virions and the loss of the HIV-1 producing cells as the drug blocks substantially new cycles of infection. Treatment with ABT-538 reduces the destruction, mediated by viruses, of CD4 lymphocytes. The combination of this treatment with DP-178 and / or DP-107, which inhibit at least the primary stage of HIV infection, viral fusion, would very likely have synergistic effects and a significant clinical impact. DP-178 or DP-107 or a pharmaceutically acceptable derivative thereof can also be used in combination with a class of anti-VlH drugs that interfere with the 5"-RNAm processes, eg ribavirin. (Ribavirin (Virazole ) by Viratel Inc.) Although the mechanism of action of ribavirin is not clear, it is assumed that this drug competes with guanosine during the formation of the hat structures of the mRNA and / or interferes with the functional methylation of these molecules. , which can escape the inhibition of viral fusion by means of DP-178 and / or DP-107, would be blocked by ribavarin and, by this, would present synergy of the anti-VlH mechanism of DP-178 and / or DP-107 and ribavarin - In addition, DP-178, DP-107 or a pharmaceutically acceptable derivative thereof can be used in combination with therapeutic agents such as Amphotericin B (Fungizone, obtained from Gibco) an antifungal antibiotic microlens polyene which interacts with the sterols and binds to these irreversible way. Amphotericin B represents a unique class of agents that are active against a variety of viruses covered by lipids, which includes HIV. Although amphotericin exhibits severe toxicities in vivo, the methyl ester form of this drug also exhibits anti-HIV activity and has a low cellular toxicity profile, in vitro. Thus, Amphotericin B or its methyl ester can be used in combinatorial therapy with DP-178, DP-107 or a pharmaceutically acceptable derivative thereof. This combination allows the physician to employ a lower, ie less toxic, dose of Amphotericin B or its methyl ester without concern for antiviral activity since it is used in conjunction with antiviral peptides DP-178 or DP-107. In accordance with the present invention, DP-178 or DP-107 or a pharmaceutically acceptable derivative thereof can also be used in combination with inhibitors of glycoprotein processes, such as castonospermine (Boehringer Mannheim). Castanospermine is a plant alkaloid that inhibits glycoprotein processes, and acts as an anti-VlH since HIV contains two densely glycosylated proteins, gpl20 and gp41. The glycosylation of the protein plays an important role in the interaction of gpl20 with CD4. Under conditions of infection by progeny virions synthesized in the presence of castanospermine, the ineffectiveness of HIV was attenuated. Therefore, it is very likely that DP-178, DP-107 or a pharmaceutically acceptable derivative thereof, in combination with castanospermine would act synergistically to inhibit viral entry and consequently attenuate the infection. Preferred combinations that are used within the HIV treatment methods include the use of an "effective amount of DP-178, DP-107 or a pharmaceutically acceptable derivative thereof and an effective amount of ddl.; the use of an effective amount of DP-107, DP-178 or a pharmaceutically acceptable derivative thereof and an effective amount of 3TC; and the use of an effective amount of DP-107, DP-178 or a pharmaceutically acceptable derivative thereof and an effective amount of ribavarin. Other preferred combinations for use within the HIV treatment methods include the use of an effective amount of DP-107, DP-178 or a pharmaceutically acceptable derivative thereof and an effective amount of beta-interferon. Yet another combination that can be used with HIV treatment methods includes the use of an effective amount of DP-107, DP-178 or a pharmaceutically acceptable derivative thereof and an effective amount of protease inhibitors. To evaluate the potential therapeutic efficacy of DP-178, DP-107 or a pharmaceutically acceptable derivative thereof in combination with the antiviral therapeutic agents described in the foregoing, these combinations can be tested for antiviral activity according to the methods known in the art. technique. For example, the ability of the DP-178 and AZT combination to inhibit HIV cytotoxicity, syncytia formation, reverse transcriptase activity or the generation of viral RNAs or proteins can be tested in vitro, as described in Example 6. . 2.1. Therapeutic Uses of HIV Inhibitory Combinations The combined therapy of DP-178 or enhanced or synergistic DP-107 as described above can be used according to the invention in vivo to prevent the formation of syncytites and the production of HIV virions and, in this way, inhibit the progress of HIV within an exposed patient. The combinatorial therapy of the present invention is also useful for alleviating or treating diseases associated with immunosuppressed patients infected with HIV. For example, antiviral peptides DP-178, DP-107 or pharmaceutically acceptable derivatives thereof can be used in combination with antifungal, antiviral agents with effects against HBV, EBV, CMV, and other opportunistic infections including TB. The antiviral peptide of the present invention, DP-178, DP-107 or pharmaceutically acceptable derivatives thereof, are preferably used against HIV infection. Effective doses of combinatorial therapy as described below, can be formulated in suitable pharmaceutical carriers and can be administered by any suitable means including, but not limited to, injection (eg, intravenous, intraperitoneal, intramuscular, subcutaneous). , etc.), by absorption through epithelial or mucocutaneous coatings (for example, epithelial coatings of the oral, rectal and vaginal mucosa, nasopharyngeal mucosa, intestinal mucosa, etc.); orally, transdermally or any other means available within the pharmaceutical technique. . 3. Pharmaceutical Formulations, Dosage and Administration Modes 5.3.1. Pharmaceutical Compositions The pharmaceutical compositions of the invention which are useful in the treatment or prevention of viral infections in humans contain as active agent DP-178, DP-107 or a pharmaceutically acceptable derivative thereof, and at least one other therapeutic agent, as be another antiviral. The pharmaceutical compositions of the present invention provide combination therapy which may have additive and / or synergistic effects. Preferably, pharmaceutical compositions containing DP-178 or DP-107 or pharmaceutically acceptable derivatives thereof also contain at least one other antiviral agent, such as inhibitors of reverse transcriptase, protease inhibitor, inhibitors of mRNA processes , inhibitors of protein glycosylation and inhibitors of viral fusion. These agents include, but are not limited to, nucleoside analogs or chain terminators (eg, dideoxynucleosides). Additional suitable therapeutic agents that can be used in combination therapy with DP-178 or DP-107 or a pharmaceutically acceptable derivative thereof within the scope of the invention include, but are not limited to, 2-deoxy-D-glucose ( 2-DGLC), deoxynojirimycin, acycloguanosine, ribavirin (Virazole, rifampicin (Rifadin®), adamantidina, rifabutin, ganciclover, (DHPG), fluoroiodoaracitocina, idoxurina, trifluorothymidine, adenine arabinoside (ara-A), ara-AMP, bromovinyldeoxyuridine, bromovinilarauracilo ( BV-araU by Bristol-Meyer Squibb (1-beta-D-arabinofuranoside-E-5- [2-bromovinyl] uracil)) ri antadine, arildone, diaryl indin, (S) - (p-nitrobenzyl-) 6-thioinosine and phosphonoformate The novel pharmaceutical compositions comprised by the present invention include, but are not limited to, DP-178, DP-107 or a pharmaceutically acceptable derivative and picine raffle (rifadin); DP-178 or DP-107 and AZT; DP -178 or DP-107 and ddl; DP-178 or DP-107 and ddC; DP-178 or DP -107 and adamantidine; DP-178 or DP-107 and acicloguanosine; DP-178 or DP-107 and 2-deoxy-D-glucose, DP-178 or DP-107 and deoxynojirimycin; DP-178 or DP-107 and interferon-a and DP-178 or DP-107 and ganciclovir. The present invention also encompasses pharmaceutical compositions containing DP-178 or DP-107 or a pharmaceutically acceptable derivative, and optionally more than one additional therapeutic compound. The peptides of the present invention can be administered using techniques well known to those skilled in the art. Preferably, the agents are formulated and administered systemically. Techniques for formulation and administration can be found in "Remington's Pharmaceutical Sciences," 18"'ed., 1990, Mack Publishing Co., Easton, Pa. Suitable routes may include oral, rectal, transmucosal or intestinal administration.; parenteral administration, including intramuscular, subcutaneous, intraoral, as well as intratracheal, direct intraventricular, intravenous, intraperitoneal, intranasal or intraocular injections, just to name a few. The most preferred is intravenous administration. For injection, the agents of the invention can be formulated in aqueous solutions, preferably in physiologically compatible buffer solutions such as Hank's solution, Ringer's solution or physiological saline buffer solution. For administration through the mucosa, suitable penetrants are used in the formulation for the barrier to be penetrated. In general, these penetrants are known in the art. In addition, the peptides can be used as a prophylactic measure in previously uninfected individuals after acute exposure to an HIV virus. Examples of this prophylactic use of the peptides may include, but are not limited to, prevention of mother-to-child transmission of the virus and other provisions where the likelihood of HIV transmission exists, such as, for example, Accidents in health care facilities where workers are exposed to blood products that contain HIV. The peptides of the invention in these cases can serve the function of a prophylactic vaccine, wherein the host elevates the antibodies against the peptides of the invention, which then serve to neutralize the HIV viruses by, for example, inhibiting an infection of HIV greater. The administration of the peptides of the invention as a prophylactic vaccine, therefore, would comprise administering to a host an effective concentration of peptides to elicit an immune response that is sufficient to neutralize HIV, for example, by inhibiting the ability of HIV to infect the cells. The exact concentration will depend on the specific peptide that is administered, but can be determined using standard techniques to test the development of an immune response that are well known to those of ordinary skill in the art. Peptides that are used as vaccines are usually administered intramuscularly. The peptides can be formulated with a suitable adjuvant to improve the immune response. These adjuvants may include, but are not limited to, mineral gels such as aluminum hydroxide; surface active substances such as lysolecithin, pluronic polyols, polyanions; other peptides; oil emulsions; and adjuvants potentially useful for humans such as BCG and Corynebacterium parvum. Various methods can be used to introduce the vaccine formulations described herein. These methods include, but are not limited to, the oral, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous or intranasal routes.

The effective doses of the peptides of the invention to be administered can be determined by methods well known in the art that provide parameters such as biological half-life, bioavailability and toxicity. According to the data presented below in Section 6, DP-178, for example, can prove its efficacy in vivo in doses necessary to reach circulating levels of lOmg per ml of peptide. . 3.2. Dosage During treatment in mammals, including humans, having a viral infection, a therapeutically effective amount of DP-178, DP-107 or a pharmaceutically acceptable derivative is administered, i.e., a dose sufficient to inhibit viral replication. For example, DP-178 or DP-107 can be administered as an infusion from 0.1 mg / kg to 1.0 mg / kg per day for about 12 weeks. A preferable dose is from 20 mg to 35 mg; the equivalent daily dose of DP-178 or DP-107 or a pharmaceutically acceptable derivative thereof based on the surface area is from about 7 mg to 70 mg. The most preferable dose is about 20 mg to 35 mg for about 12 weeks. Doses of DP-178, DP-107 or a pharmaceutically acceptable derivative should be administered at intervals from about once a day to four times a day and preferably from about once every two days to once a day. A preferred dose is administered to achieve maximum plasma concentrations of DP-178, DP-107 or a pharmaceutically acceptable derivative thereof from about 1 mg / ml to 10 mg / ml. This can be achieved by the sterile injection of a 2.0% solution of the ingredients administered in buffered saline (it is possible to use any suitable saline solution known to those skilled in the art of chemistry). Desirable blood concentrations can be maintained by continuous infusion of DP-178 or DP-107 as determined by plasma concentrations measured by HPLC (CIAR). The effective amounts of the therapeutic agents, for example, antivirals that are used in combination with DP-178, DP-107 or a pharmaceutically acceptable derivative thereof are based on the recommended doses known to those skilled in the art for the various antivirals. For example, doses for AZT, ddI and interferon-Beta can be found in standard medical reference texts. In addition, do§is for other therapeutic agents, including antivirals, are reported in the literature, for example, ABT-538 is administered orally from 600-1,200 mg / day on day 1 and daily after it ( Ho, et al., 1995, Nature, 373: 123-126). These recommended or known concentrations of preference will be reduced by 10% to 50% of the mentioned dose after testing the effectiveness of these dosages in combination with DP-178, DP-107 or a pharmaceutically acceptable derivative, using the assays described in Section 5.4 below. It should be noted that the attending physician will know how and when to terminate, interrupt or adjust the therapy to reduce the dosage due to toxicity, bone marrow, liver or kidney dysfunction or drug-adverse drug interaction. On the contrary, the attending physician will also know how to adjust the treatment to higher levels if the clinical response is not adequate (to prevent toxicity). A therapeutically effective dose refers to that amount of compound sufficient to lessen the symptoms or prolong the survival of a patient. The toxicity and therapeutic efficacy of these compounds can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, for example, to determine LD50 (lethal dose for 50% of the population) and ED50 (the therapeutically effective dose in 50% of the population). The proportion of the dose between toxic and therapeutic effects is the therapeutic index and can be expressed as the LD50 / ED50 ratio. Compounds that have large therapeutic indices are preferred. The data obtained from these cell culture assays and animal studies can be used to formulate a range of doses for human use. The dosage of these compounds is preferably within a range of circulating concentrations that includes the EDSO with little or no toxicity. The dosage may vary within this range depending on the dosage form used and the route of administration used. For any compound used in the method of the invention, the therapeutically effective dose can be calculated initially - 'from the cell culture assays. A dose can be formulated in animal models to achieve a circulating plasma concentration range that includes the IC50 (ie, the concentration of the test compound that achieves a medium-maximal inhibition of the production of IT from infected cells in comparison With an untreated control as the cell culture is determined, this information can be used to more accurately determine the useful dose in humans.The plasma concentrations can be measured, for example, by high-performance liquid chromatography (HPLC). . . 4. Pharmaceutical Formulations and Routes of Administration Pharmaceutical compositions containing DP-178, DP-107 or a pharmaceutically acceptable derivative can be administered to a human patient, by themselves or in pharmaceutical compositions where they are mixed with carriers or excipients (s). ) suitable in doses to treat a viral infection, in particular an HIV infection. The techniques for the formulation and administration of the compounds of the present application can be found in "Remington" s Pharmaceutical Sciences, "Mack Publishing Co., Easton, PA, latest edition, as demonstrated in the example presented below in In Section 6, the antiviral activity of * -the peptides of the invention may show a specific type and subtype specificity, ie, the specific peptides may be effective to inhibit the activity of specific viruses only.This feature of the invention has many advantages One of these advantages, for example, lies in the field of diagnosis, where one can use the antiviral specificity of the peptide of the invention to determine the identity of a viral isolate.With respect to HIV, one can easily determine whether an isolate A viral strain consists of a strain of HIV-1 or HIV-2, for example, uninfected CD-4 + compounds can be co-infected with an isolate that the peptide DP-178 (SEQ ID: 1) has been identified with an HIV content, after which the retriviral activity of the cellular supernatants can be tested using, for example, the techniques described in Section 5.2. These isolates whose retriviral activity is completely or almost completely inhibited contain HIV-1. Those isolates whose viral activity does not change or only reduce by a small amount, can be considered not to contain HIV-1. An isolate such as this can then be treated with one or more of the other DP-178 peptides of the invention, and subsequently it can be tested for its viral activity to determine the identification of the viral isolate. The use of pharmaceutically acceptable carriers to formulate the compounds of the present invention described for the practice of the invention in the doses suitable for systemic administration is within the scope of the invention. With a suitable choice of carrier and adequate manufacturing practice, the compositions of the present invention, in particular those formulated as solutions, can be administered parenterally, such as by intravenous injection. The compounds can be easily formulated using pharmaceutically acceptable carriers well known in the art in doses suitable for oral administration. These carriers allow the compounds of the invention to be formulated as tablets, pills, capsules, liquids, gels, syrups, suspensions, slurries, and the like, for oral ingestion of a patient to be treated.

Suitable routes of administration may, for example, include oral, rectal, transmucosal or intestinal administration; parenteral administration, including intramuscular, subcutaneous, intramedullary injections, as well as intratracheal, direct intraventricular, intravenous, intraperitoneal, intranasal or intraocular injections; transdermal, topical, vaginal and the like. Dosage forms include, but are not limited to tablets, troches, dispersions, suspensions, suppositories, solutions, capsules, creams, patches, mini-pumps and the like The pharmaceutical compositions for use in accordance with the present invention, of this Thus, they can be formulated in a conventional manner using one or more physiologically acceptable carriers containing excipients and auxiliaries that facilitate the processing of the active compounds in the preparations that can be used pharmaceutically.The appropriate formulation will depend on the chosen route of administration. injection, the agents of the invention can be formulated in aqueous solutions, preferably in physiologically compatible buffer solutions such as Hank's solution, Ringer's solution or physiological saline buffer solution. For transmucosal administration, suitable penetrants are used in the formulation for the barrier to be lost. These penetrants are generally known in the art. For oral administration, the compounds can be formulated easily by combining the active compounds with pharmaceutically acceptable carriers known in the art. These carriers allow the compounds of the invention to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions and the like, for the oral ingestion of a patient to be treated. Pharmaceutical preparations for oral use can be obtained from solid excipients, optionally by grinding a resulting mixture and processing the granule mixture, after the addition of suitable auxiliaries, if desired, to obtain tablets or dragee cores. Suitable excipients are, in particular, fillers such as sugars, including lactose, sucrose, mannitol or sorbitol.; cellulose preparations, such as, for example, corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth gum, methyl cellulose, hydroxypropylmethyl cellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidone (PVP). If desired, disintegrating agents may be added, such as cross-linked polyvinylpyrrolidone, agar or alginic acid or salts thereof such as sodium alginate.

Dragee cores are provided with suitable coatings. For this purpose, concentrated sugar solutions can be used, which optionally may contain gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol, and / or titanium dioxide, lacquer solutions and suitable organic solvents or solvent mixtures. The dyes or pigments can be added to the tablets or dragee coatings for identification or to characterize different combinations of the doses of the active compounds. Pharmaceutical preparations that can be used orally include soft-fit capsules made of gelatin, as well as sealed, soft capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. The soft-fit capsules may contain the active ingredients in admixture with fillers such as lactose, binders such as starches and / or lubricants such as talc or magnesium stearate and, optionally, stabilizers. In soft capsules, the active compounds can be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin or liquid polyethylene glycols. It is also possible to add stabilizers. All formulations for oral administration should be in doses suitable for this administration.

For buccal administration, the compositions may take the form of tablets or lozenges formulated in the conventional manner. For administration by inhalation, the compounds for use in accordance with the present invention are conveniently administered in the form of an aerosol spray presentation from pressurized containers or a nebulizer, with the use of suitable propellants, for example, dichloro difluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol, the dosage unit can be determined by providing a valve to supply a metered amount. Capsules and cartridges of, for example, gelatin for use in an inhaler or insufflator can be formulated with a content of a powder mixture of the compound and a suitable powder base such as lactose or starch. The compounds can be formulated for parenteral administration by injection, for example, by bolus injection or continuous infusion. Formulations for injection may be presented in unit dosage form, for example, in ampules or in multi-dose containers, with an added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and / or dispersing agents. Pharmaceutical formulations for parenteral administration include aqueous solutions of the active compounds in a water soluble form. In addition, suspensions of the active compounds can be prepared as suitable oil suspensions for injection. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil or synthetic fatty acid esters such as ethyl oleate or triglycerides, or liposomes. Aqueous suspensions for injection may contain substances that increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol or dextran. Optionally, the suspension may also contain suitable stabilizers or agents that increase the solubility of the compounds to allow the preparation of highly concentrated solutions. Otherwise, the active ingredient may be in powder form for constitution with a suitable vehicle, eg, sterile, pyrogen-free water, before use. The compounds can also be formulated in rectal compositions such as suppositories or retention enemas, for example, with a content of conventional suppository bases such as cocoa butter or other glycerides. In addition to the formulations already described, the compounds can also be formulated as a depot preparation. These prolonged activity formulations can be administered by implantation (e.g., subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, the compounds can be formulated with suitable polymeric or hydrophobic materials (for example, as an emulsion in an acceptable oil) or in ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly salt soluble. A pharmaceutical carrier for the hydrophobic compounds of the invention is a cosolvent system consisting of benzyl alcohol, a non-polar surfactant, an organic water miscible polymer and an aqueous phase. The co-solvent system can be the co-solvent VPD system. The VPD system is a solution of benzylic alcohol at 3% w / v, polysorbate 80, non-polar surfactant at 8% w / v and polyethylene glycol 300 at 65% w / v, brought to a volume in absolute alcohol. The VPD co-solvent system (VPD: 5W) consists of VPD diluted 1: 1 with a dextrose solution in 5% water. This co-solvent system dissolves hydrophobic compounds well, and in itself produces low toxicity in systemic administration. Naturally, the proportions of a co-solvent system can vary considerably without destroying its solubility and toxicity characteristics. In addition, the identity of the components of the co-solvent may vary: for example, it is possible to use other non-polar surfactants of low toxicity instead of polysorbate 80; the size of the polyethylene glycol fraction can be varied; it is possible to substitute other biocompatible polymers with polyethylene glycol, for example, polyvinylpyrrolidone; and other sugars or polysaccharides can replace dextrose. The pharmaceutical compositions may also contain suitable solid phase or gel carriers or excipients. Examples of these carriers or excipients include, but are not limited to, calcium carbonate, calcium phosphate, various sugars, starches, cellulose derivatives, gelatin and polymers such as polyethylene glycols. Pharmaceutical compositions suitable for use in the present invention include compositions wherein the active ingredients are contained in an effective amount to achieve their intended purpose. The determination of the effective amounts is within the ability of those skilled in the art, especially in light of the detailed description that is provided herein. . 5. Antiviral Activity Assays The antiviral activity exhibited by the combination therapy of the invention can be measured, for example, by assays performed first in vitro, such as those described below, which can test the ability of peptides to inhibit the formation of syncytia or its ability to inhibit infection by cell-free viruses. Using these assays it is possible to determine parameters such as the relative antiviral activity of the peptides, present against a certain strain of virus and / or the peptide-specific inhibitory activity of the strain. A cell fusion assay can be used to test the ability of peptides to inhibit HIV-induced syncytia formation in vitro. This assay may involve culturing uninfected CD-4 + cells (such as Molt or CEM cells). for example) in the presence of cells chronically infected with HIV and a therapeutic agent to be tested. For each combinatorial therapy, a range of concentrations can be tested. This range should include a control culture in which no peptide is added. Standard conditions for cultivation are used, well known to those of ordinary skill in the art. After incubation for a suitable period (24 hours at 37 ° C, for example) the culture is examined under the microscope for the presence of giant ultinucleated cells, which are indicative of cell fusion and syncytium formation. A reverse transcriptase (TI) assay can be used to test the ability of peptides to inhibit infection of CD-4 + cells by cell-free HIV in combination with another antiviral agent. This assay may consist of culturing an appropriate concentration (i.e., TCID of virus and CD4 + cells in the presence of the peptide and the antiviral in the combination to be tested.) Culture conditions well known in the art are used. As mentioned before, it is possible to use a range of concentrations of the peptide, in addition to a control culture in which no peptide is added.After incubation for a suitable period (for example, 7 days) of culture, a cell-free supernatant using normal procedures, and tested for the presence of IT activity as a measure of successful infection.The activity of IT can be tested using standard techniques such as those described, for example, in Goff et al. (Goff, S. et al., 1981, J. Virol. 38: 239-248) and / or Willey et al. (Willey, R. et al., 1988, J. Virol. 62: 139 -147.) These references are incorporated herein by reference in your integrity Normal methods that are well known to those skilled in the art that can be used to test non-retriviral activity. See, for example, Pringle et al. (Pringle, C.R. et al., 1985, J. Medical Virology 17: 377-386) for an analysis of the assay techniques of the activity of the respiratory syncytial virus and the parainfluenza virus. In addition, see, for example, "Zinserr Microbiology", 1988, Joklik, W.K. et al., eds., Appleton & Lange, Norwalk, CT, 19 ed., For a general review of these techniques. These references are incorporated herein by reference in their entirety. . 5.1 Tests of active antiviral compounds in different stages of HIV-l infection Three separate in vitro trials for the study of active antiviral compounds in different stages of HIV infection (acute, co-culture and chronic) are well known to experts in the art (Lambert et al., 1993, Antiviral Res. 21: 327-342). These assays can be used to assess the effects of DP-178, DP-107 or a pharmaceutically acceptable derivative thereof in combination with one of the antiviral agents described. All assays are carried out in triplicate in 24-well plates (Nunc.) The five-fold dilution series of the inhibitor are made in 100% DMSO to produce final 200x concentrations. The addition of a 1/200 volume of dilutions to the culture wells results in a final concentration of 0.5% DMSO and the desired concentration of the inhibitor. The experiments are carried out with dilutions of constant proportion of the two inhibitors, (ie, 1:10 or 1:40, AZT: DP-178) or where the concentrations are varied. First, the acute infection assay modeles the rapid replication and cytopathic effects that contribute to the loss of CD4 + cells in vivo. The treatment assay of acutely infected Molt4 cells shows that antiviral compounds are effective in inhibiting the spread of HIV-1 infection in T cells. For these assays, uninfected Molt4 cells 3xl04 per well are infected with HIV TCID50. -l (strain LA1). Standard solutions of the inhibitors are prepared in DMSO at 100% and are added on day 0, immediately after the virus absorption period of 1.5 hours. The cultures are fed back on days 1 and 4 with medium with a content of the same inhibitor concentration. Samples are harvested on day 7. Second, chronically infected cells, with an integrated provirus content and having moderate to low levels of continuous viral expression, are most likely to represent in vivo deposits of infectious virions, which ultimately contribute to the advance of the illness. The chronically infected cells are washed three times in growth medium and plated at a density of 6x1 cells per well. The inhibitors are added on day zero. The cultures are fed on days 1 and 3 with growth medium with a content of the same inhibitor concentration. The trials are counted on day 5. Third, the co-culture trial that is used in these studies is a relevant model of infection in vivo since it includes cell-to-cell fusion and dispersion as well as cell-free dispersion of HIV-l inside? culture. For this assay, 3x10 'uninfected Molt4 cells are co-cultured with chronically infected H9 / LA1 or CEM / LA1 cells 3x103 cells per well in 24-well plates. The inhibitors are added on day zero, and the test plates are fed on days 1 and 3 with growth medium containing the inhibitors. The assay is harvested on day 5. Antiviral activity is measured by various parameters: the analysis of the Western protein bands of packed cells from the tested cultures, the levels of the TI and the levels of the p24 antigen in the supernatant. The effects of the combination drug are calculated using the multiple drug analysis method of Chou and Talalay (Chou and Talalay, 1984, Adv. Enzyme Regul. 22: 27-55) and the computer program 'Dose-Effect Analysis whit microcomputers? ) (Chou and Chou, 1987, software and manual, p9-64, Elsevier Biosoft, Cambridge, UK) using the equation: CI = _ (D + _ (D + a (D)? (D) 2 (Dx)! (Dx), (Dx (D), where Cl is the combination index, (Dx) x is the dose of drug 1 necessary to produce x percent effect only, (D) x is the dose of drug 1 needed to produce the same x percent effect in combination with (D) 2. The values of (Ox.) ¿And (O) are obtained in the same way from drug 2. The value of alpha is determined from the graph of the dose effect curve using the equation of the average effect: fa / fu - (D / Dm) m where fa is the fraction affected by dose D, fu is the uninfected fraction, Dm is the dose needed for 50% of the effect and is the slope of the dose-effect curve. For mutually exclusive medications (ie, similar modes of action), both drugs alone and their parallel lines on the graph of the mean effect. Mutually non-exclusive drugs (ie, independent mode of action) will give parallel lines on the graph of the average effect, but in mixing they will produce a concave curve upwards. If the agents are mutually exclusive, alpha is 0, and if these are mutually exclusive, a is 1. The values obtained assuming no mutual exclusivity will always be slightly higher than mutually exclusive medications. Cl values < 1 indicate synergy, values > 1 indicate antagonism and values equal to 1 indicate additive effects. The effects of the combination drug are also calculated using the MacSinergy computer program (Pritchard and Shipman, 1990, Antiviral Research 14: 181-206). This computer program allows the three-dimensional graphic analysis of drug-medication interactions. The amount of synergy observed with the combinations of the antiviral compounds is calculated by the MacSynergy program and is represented by a three-dimensional bar graph in which the percentage of the drug interaction is plotted against the drug concentrations. The amount of synergy is represented by the heights of the bars in the graph and the antagonism is plotted as a negative value below the base of the graph. 6. Example: DP-178 (SEQ ID: 1) is a potent inhibitor of HIV-1 infection. In this example, DP-178 (SEQ ID: 1) demonstrates that it is a potent inhibitor of CD cell-cell fusion. -4+ HIV-1 mediated and infection by cell-free virus. In the fusion assay, this peptide completely blocks virus-induced syncytia formation in concentrations of 1-10 ng / ml. In the infectivity assay, the inhibitory concentration is somewhat higher, blocking the infection at 90 ng / ml. It is further demonstrated that DP-178 (SEQ ID: 1) shows that the antiviral activity of DP-178 (SEQ ID: 1) is highly specific for HIV-1. Additionally, a synthetic peptide, DP-185 (SEQ ID: 3) which represents a homologue of DP-178 from HIV-1 also blocks syncytia mediated by HIV-1. 6. 1. Materials and methods 6.1.1. Synthesis of peptides The peptides wsited using Fast Moc chemistry on an Applied Biosystems Model 431a peptide synthesizer. The amidated peptides wprepared using the Rink resin (Advanced Chemtech) while the peptides with a content of terminal free carboxy groups wsynthesized in a Wang resin (p-alkoxybenzyl alcohol) (Bachen). The first residues wcoupled to the appropriate resin and the subsequent residues wcoupled singly. Each coupling step was followed by the formation of the cap or hat with acetic anhydride. The peptides wseparated from the resin by treatment with trifluoroacetic acid (TFA) (10 ml), H20 (0.5 ml), thioanisole (0.5 ml), ethanedithiol (0.25 ml), and crystalline phenol (0.75 g). The purification was carried out by reverse phase HPLC. Samples with approximately 50 mg of the impure peptide wsubjected to chromatography on a Waters Delta Pak C18 column (19 mm x 30 cm, 15 μ spherical) with a linear gradient; H20 / acetonitrile 0.1% TFA. The lyophilized peptides wstored dried and the peptide solutions wmade in water at approximately 1 mg / ml. Electrospray mass spectrometry produced the following results: DP-178 (SEQ ID: 1): 4491.87 (calculated 4491.94); DP-180 (SEQ ID: 2): 4491.45 (calculated 4491.94); DP-185 (SEQ ID: 3): not made (calculated 4546.97). 6. 1.2. Virus The HIV-lua virus was obtained from R. Gallo (Popovic, M. et al., 1984, Science 224: 497-508) and propagated in CEM cells cultured in RPMI 1640 with a content of 10% fetal bovine serum. . The supernatant of the infiltrated CEM cells was passed through a 0.2 μ filter and the infectious titer was calculated in an icroinfectivity assay using the AA5 cell line to support the replication of the virus. For this purpose, 25 μl of virus dilution series was added to 75 μl AA5 at a concentration of 2xl05 / ml in a 96-well microtiter plate. Each dilution of virus was tested in triplicate. The cells wcultured for 8 days by the addition of fresh medium every third day. On day 8 after infection, the supernatant samples wtested for virus replication evidenced by the activity of the reverse transcriptase released in the supernatant. The TCIDbü was calculated according to the formula of Reed and Muench (Reed, L.J. et al., 1938, A. J. Hyg. 27: 493-497). The titer of the HIV-lu and HIV-1MN standard solutions used in these studies, when measured in the AA5 cell line, was approximately 1.4xl06 and 3.8x10 ^ TCID5o / ml, respectively. 6. 1.3. Cell fusion assay Approximately 1X10A Molt cells wincubated with lxlO'1 CEM cells chronically infected with HIV-ILM virus in 96-well plates (medium-area cluster plates, Costar, Cambridge, MA) in a final volume of 100 μl of culture medium, as previously described (Matthews, TJ et al., 1987, Proc. Nati, Acad. Sci. USA 84: 5424-5428). The peptide inhibitors wadded in a volume of 10 μl and the cell mixtures wincubated for 24 h at 37 ° C. During this time, the multinucleated giant cells wcalculated by microscopic examination with a magnification of 40x which allowed the visualization of the entire well in a single field. 6. 1.4. Cell-free virus infection assay Synthetic peptides were incubated at 37 ° C with 247 TCIDI units ,? (for the experiment depicted in Figure 2), or 62 TCID ^ u (for the experiment depicted in Figure 3) of HIV-1 ^ or 25 TCID ^ or HIV-2NIH2 and CD4 + CEM cells with peptide concentrations of 0.04, 0.4, 4.0 and 40 μg / ml for 7 days. The resulting reverse transcriptase (TI) activity in the counts per minute was determined using the assay described below in Section 6.1.5. See, Reed, L.J. et al., 1938, Am. J. Hyg. 27: 493-497 for the explanation of TCID50 calculations. 6. 1.5. Reverse transcriptase assay The micro-reverse transcriptase (TI) assay was adopted by Goff et al. (Goff, S. et al., 1981, J. Virol. 38: 239-248) and Wiiley et al. (Willey, R. et al., 1988, J. Virol. 62: 139-147). The supernatants of the virus / cell cultures were adjusted to 1% with Triton-XIOO. A lOμl sample of the supernatant was added to 50μl of an IT cocktail in a 96 well U-shaped microtiter plate and the samples were incubated at 37 ° C for 90 min. The IT cocktail contained 75 mM KCL, 2mM dithiothreitol, 5 mM MgCl 2, 5 μg / ml poly A (Pharmacia, cat No. 27-4110-01), 0.25 units / ml oligo dT (Pharmacia, Cat. 27-7858-01), 0.05% NP40, 50 ml Tris-HCl, pH 7.8, 0.5 μM non-radioactive dTTP, and 10 μCi / l! P-dTTP (Amersham, cat No. PB.10167). After the incubation period, 40 μl of the reaction mixture was applied to a membrane Schleicher and Schuell (S + S) NA45 (or paper dDE81) saturated in buffer solution 2 x SSC (0.3 M NaCl and 0.003 M citrate). sodium) maintained in a? + S Minifold on a sheet of filter paper GB003 (S + S), with partial vacuum applied. Each well of the manifold was washed four times with 200 μl of 2 x SSC, with total vacuum. The membrane was removed from the manifold and washed twice more in a Pyrex dish with an excess of 2 x SSC. Finally, the membrane was drained on absorbent paper, placed on Whatman # 3 paper, covered with Saran and exposed to the film overnight at -70 ° C. 6. 1. Results 6.2.1. Peptide inhibition of syncytia formation, induced by infected cells Initial screening for antiviral activity assessed the ability of peptides to block syncytia formation induced by overnight co-culture of non-infected Molt4 cells with chronically infected CEM cells with VUH-1. The results of the various experiments are presented in this description. In the first of these experiments the series of concentrations of peptide DP-178 (SEQ ID: 1) between 10 μg / ml and 12.5 ng / ml was tested for blocking the cell fusion process. For these experiments, CEM cells chronically infected with HIV-1, HIV-IM, HIV-1, or HIV-1St2 were co-cultured overnight with uninfected Molt4 cells. The results (Figure 4) show that DP-178 (SEQ ID: 1) provided complete protection against each of the HIV-1 isolates at the lowest concentration of DP-178 (SEQ ID: 1) used. For the inhibition of the lowest concentration that was tested was 12.5 ng / ml. For all other HIV-1 viruses, the lowest concentration of DP-178 (SEQ ID: 1) used in this study was 100 ng / ml. A second peptide, DP-180 (SEQ ID: 2) with a content of the same amino acid residues as DP-178 (SEQ ID: 1), but arranged in a random order, showed no evidence of antifusogenic activity even in a high concentration of 40 μg / ml (Figure 4). These observations indicate that the inhibitory effect of DP-178 (SEQ ID: 1) is specific to the primary sequence and is not related to non-specific peptide / protein interactions. The actual endpoint (ie, the lowest effective inhibitory concentration) of the inhibitory action of DP-178 is within the range of 1-10 ng / ml. The following series of experiments included the preparation and testing of a homolog of DP-178 (SEQ ID: 1) for its ability to inhibit HIV-1 induced syncytium formation. As shown in Figure 1, the DP-185 sequence (SEQ ID: 3) is slightly different from DP-178 (SEQ ID: 1) in that its primary sequence is taken from the HIV-1SF2 isolate and contains some differences in amino acids relative to DP -178 (SEQ ID: 1) near the N terminal. As shown in Figure 4, DP-185 (SEQ ID: 3) m exhibits inhibitory activity even at 312.5 ng / ml, the lowest concentration tested. The next series of experiments included a comparison of the inhibitory activity of HIV-1 and HIV-2 by DP-178 (SEQ ID: 1). As shown in Figure 5, DP-178 (SEQ ID: 1) blocked HIV-1 mediated syncytia formation at peptide concentrations below 1 ng / ml. however, DP-178 (SEQ ID: 1) failed to block HIV-2-mediated syncytia formation at concentrations as high as 10 μg / ml. This surprising 4 log selectivity of DP-178 (SEQ ID: 1) as an inhibitor of cell fusion mediated by HIV-1 demonstrates an unexpected specificity to HIV-1 in the action of DP-178 (SEQ ID: 1). Inhibition of HIV-1 mediated cell fusion by DP-178 (SEQ ID: 1), but the inability of the peptide to inhibit HIV-2 mediated cell fusion in the same cell type at the tested concentrations provides more evidence for the high degree of selectivity associated with the anti-viral action of DP-178 (SEQ ID: 1). 6. 2.2. Peptide Inhibition of Cell-Free Virus Infection The DP-178 (SEQ ID: 1) was then tested for "its ability to block infection of CEM CD-4 + cells by the cell-free HIV-1 virus. The results, which are shown in Figure 2, are from an experiment in which DP-178 (SEQ ID: 1) was tested for its ability to block infection of CEM cells by an HIV-IIAI isolate. in the experiment were three control peptides, DP-116 (SEQ ID: 9), DP-125 (SEQ ID: 8) and DP-118 (SEQ ID: 10) .The DP-116 (SEQ ID: 9) represents a peptide that previously was shown to be inactive using this assay, and DP-125 (SEQ ID: 8; Wild, C. et al., 1992, Proc. Nati. Acad. Sci., EU, 89: 10,537), and DP- 118 (SEQ ID: 10) are peptides that previously showed to be active in this assay.Each concentration (0, 0.04, 0.4, 4 and 40 μg / ml) of peptide was incubated with 247 units TCID = or HIV-1A virus? and CEM cells After 7 days of culture and The cell-free supernatant was tested for the presence of IT activity as a measure of successful infection. The results shown in Figure 2 demonstrate that DP-178 (SEQ ID: 1) inhibited the de novo infection process mediated by HIV-1 viral isolate at concentrations as low as 90 ng / ml (IC50 = 90 ng / ml) . In contrast, the two positive control peptides, DP-125 (SEQ ID: 8) and DP-118 (SEQ ID: 10) had concentrations above 60 times plus IC 50m of about 5 μg / ml. In a separate experiment, the inhibitory action of DP-178 (SEQ ID: 1) against HIV-1 and HIV-2 was tested with CEM and HIV-1 P HIV-1NIH ^ cells. In these experiments, 62 TCID50 units of HIV-lua or 25 units of GCID50 of HIV-2NIHZ were incubated for 7 days. As can be seen in Figure 3, DP-178 (SEQ ID: 1) inhibited HIV-1 infection with an IC 50 of about 31 ng / ml. In contrast, DP-178 (SEQ ID: 1) presented a much higher IC50 for HIV-lNi ?, thus making DP-178 (SEQ ID: 1) two more potent log as an HIV-l inhibitor than as an inhibitor of HIV-2 This finding is consistent with the results of the fusion inhibition assays, described above, in Section 6.2.1, and also supports a significant level of selectivity (ie, for HIV-1 over HIV-2). 7. EXAMPLE: HIV INHIBITOR, DP-178 (SEQ ID: 1), IS NON-CITOTOXIC In this example, the synthetic 36-amino acid peptide inhibitor, DP-178 (SEQ ID: 1) is shown to be non-cytotoxic for cells in culture, even at the highest tested concentrations of the peptide (40 μg / ml). 7. 1. Materials and methods Cell proliferation and toxicity assay: Approximately 3.8 x 101 'CEM cells for each peptide concentration were incubated for three days at 37 ° C in T25 flasks. The peptides tested were DP-178 (ID? EQ: 1) and DP-116 (SEQ ID: 9), as shown in Figure 1. The concentrations used for each peptide were 0. 2.5, 10 and 40 μg / ml . Cell counts were taken at incubation times of 0, 24, 48 and 72 hours. 7. 2. Results If the potent HIV-l inhibitor, DP-178 (SEQ ID: 1) showed some cytotoxic effect, it was evaluated by testing the effects of the peptide on the proliferation and viability of the cells in the culture. CEM cells were incubated in the presence of various concentrations of DP-178 (SEQ ID: 1) and DP-116 (SEQ ID: 9), a peptide previously shown to be ineffective as an HIV inhibitor (Wild, C. et al., 1992, Proc. Nati, Acad. Sci., EU, 89: 10,537-10,541). Additionally, cells were incubated in the absence of any peptide. The results of the cytotoxicity study demonstrate that DP-178 (SEQ ID NO: 1) does not present cytotoxic effects in culture cells. As can be seen, below, in Table V, still the proliferation and viability characteristics of the cells grown for three days in the presence of higher concentrations of DP-178 (SEQ ID: 1) tested (40 μg / ml ) do not differ significantly from DP-116 (SEQ ID: 9) or from controls without peptide. Cell proliferation data are also represented in graphic form in Figure 6. As demonstrated in the Working example presented in Section 6 above, DP-178 (SEQ ID: 1) completely inhibits the formation of HIV-1 mediated syncytia at peptide concentrations between 1 and 10 ng / ml and completely inhibits cell-free viral infection in concentrations of at least 90 ng / ml. In this way, this study shows that even in peptide concentrations greater than 3 log higher than the HIV inhibitory dose, DP-178 (SEQ ID: 1) does not present cytotoxic effects.

TABLE V 8. EXAMPLE: ANTIVIRAL ACTIVITY OF TRUNCAMIENTOS Y MUTACIONES DE LOS PÉPTIDOS DP-178 AND DP-107 The example presented in this section represents a study of the antiviral activity of the truncations and mutations of DP-178 and DP-107. This demonstrates that some of these modified DP-107 and DP-178 peptides exhibit substantial antiviral activity. 8. 1. Materials and methods Anti-HIV tests: The antiviral tests performed were as described in the previous section, in Section 6.1. HIV-1 / IIIb and / or NIHZ HIV-2 isolates were used in the trials. Unless otherwise indicated in Figures 5A-C, purufuted peptides were used.

Peptides: The peptides characterized in the study and presented in this description were: 1) Figures 5A-C present peptides from the nearby region and containing the DP-178 region of the HIV-1 BRU isolate. Specifically, this region ranges from amino acid residue 615 to amino acid residue 717 of gp 41. The peptides mentioned contain truncations and / or mutations of this region that vary from the amino acid sequence of the D'p-178 sequence. In addition, some of the peptides had terminal amino- and / or carboxy groups 2) Figure 6 presents peptides exhibiting truncations of DP-107 and / or the region of gp41 that surrounds the amino acid sequence of DP-107 of the isolated from HIV-1 BRU. Some of the peptides are unblocked or biotinylated, as indicated in the figure. The blocked peptides contained an acyl group at the N terminus and an amido group at the C terminus. 8. 2. Results The antiviral anti-VlH data were obtained with group 1 of peptides from DP-178 that are mentioned in Figures 5A-C. The results of the full-length, non-mutant DP-178 peptide (defined in Figures 5A-C as T20) are shown to be 4 ng / ml. In Figure 5 some of the truncations of DP-178 showed a high level of antiviral activity, as observed by their IC ^ values. low. These include, for example, the test peptides T-50, T-624, T-636, T-641, T-645 to T-650, T-652 to T-654 and T-656. T.50 represents a test peptide that contains a point mutation, as indicated by the shaded bottom of the residue. Test peptides from HIV-1 showed different strain-specific antiviral activity in that none of the peptides tested in the NIHZ HIV-2 isolate demonstrated appreciable anti-HIV-2 antiviral activity. Among the peptides mentioned in Figure 5B, test peptides representing the amino (T-4) and carboxy (T-3) terminal moieties of DP-178 were tested. The amino-terminal peptide was not active (IC50> 400 μg / ml) while the carboxy-terminal peptide showed potent antiviral activity (ICbu = 3 μg / ml). Several additional test peptides also exhibited a higher level of antiviral activity. These included, for example, T-61 / T-102, T-217 to T-221, T-235, T-381, T-677, T-377, T-590, T-378, T-591, T-271 to T-272, T-611, T-22 to T-223 and T-60 / T-224. Some of the antiviral peptides contain point mutations and / or additions of amino acid residues that vary from the amino acid sequence of DP-178. In Figure 5C the point mutations and / or the terminal amino and / or carboxy modifications are introduced into the amino acid sequence of the DP-178. As shown in the figure, most of the listed test peptides exhibit potent antiviral activity. Truncations of peptide DP-107 (mentioned in Figure 5 as T21) were produced and tested-, as shown in Figure 6. Figure 6 also shows data related to blocked and unblocked peptides containing amino acid residues. of the gp41 region in which the DP-107 sequence resides. Most of these peptides showed antiviral activity, as evidenced by their IC¿ values ,? low. Thus, the results presented in this section demonstrate that not only the full-length DP-107 and DP-178 peptides exhibit potent antiviral activity, but the truncations of these peptides also possess substantial antiviral character. 9. EXAMPLE: POTENTIAL DP-178 / DP-107 VIS ANALOGS: ANTIVIRAL CHARACTERIZATION In the present example, simian immunodeficiency virus (SIV) DP-178-like peptides identified by using the computer-assisted search patterns described above were proven by their anti-VIS activity. It is shown that various identified peptides have potent antiviral capacity. 9. 1. Materials and methods Anti-VIS antiviral assays: The assay used here was reported in Langolis et al. (Lango? Is, A. J. et al., 1991, AIDS Research and Human Retroviruses 7: 713-720). Peptides: The peptides characterized in the present study were T-391 to T-400 peptides, as shown in Figure 7. These peptides represent a path through the DP-178-like region of the TM TM protein . Each peptide was tested in double dilution series in the range from 100 μg / ml to approximately 100 ng / ml. A well without peptide was also used for each of the tests. 9. 2. Results The data summarized in Figure 7 represent the antiviral information that was obtained through "peptide pathways" through the region similar to DP-178 (SEQ ID: 1) of the TM protein of the SIV. As shown in Figure 7, the T-391 aT-400 peptides were tested and exhibited potent antiviral activity as impure peptides. In this way, the computer-assisted searches described above, for example, the Example presented in section 8, for example, successfully identified the domains of the viral peptides representing the antiviral anti-SIV compounds representing the antiviral compounds anti-VIS highly promising. The present invention is not limited in scope by the specific embodiments described which are proposed only as illustrative of the individual aspects of the invention, and functionally equivalent methods and components are within the scope of the invention. In fact, various modifications of the invention, in addition to those shown and described herein, will be apparent to those skilled in the art from the aforementioned description and the accompanying drawings. These modifications are proposed to fall within the scope of the appended claims.

Claims (33)

1. CLAIMS A method of treating HIV infection in an individual, consisting of administering an effective amount of DP-107 or a pharmaceutically acceptable derivative thereof and an effective amount of at least one therapeutic agent.
2. A method of treating HIV infection in an individual, consisting of administering an effective amount of DP-178 or a pharmaceutically acceptable derivative thereof and an effective amount of at least one therapeutic agent.
3. The method of claim 1 or 2, wherein the therapeutic agent is an antiviral.
4. The method of claim 3, wherein the anti-VlH agent is a reverse transcriptase inhibitor, a viral protease inhibitor, a cytokine, a cytokine inhibitor, an inhibitor of glycosylation or an inhibitor of the processes of the Viral mRNA.
5. The method of claim 3, wherein the antiviral is a nucleoside analog.
6. The method of claim 5, wherein the nucleoside analogue is AZT, ddI, ddC, ddA, d4T or 3TC.
7. The method of claim 3, wherein the antiviral is interferon-a, interferon-β or interferon- ?.
8. The method of claim 2, wherein the derivative of DP-178 is a peptide from the group consisting of T-624, T-636 to T-641, T-645 to T-650, T-652 to T-654. or T- 656.
9. A method for inhibiting HIV replication, which comprises administering to the individual an effective amount of DP-107 or a pharmaceutically acceptable derivative thereof and an effective amount of at least one therapeutic agent.
10. A method for inhibiting HIV replication, which comprises administering to the individual an effective amount of DP-178 or a pharmaceutically acceptable derivative thereof and an effective amount of at least one therapeutic agent.
11. A method for inhibiting the transmission of an HIV retrovirus to a cell, which is to contact the cell with an effective amount of DP-107 or a pharmaceutically acceptable derivative thereof and an effective amount of at least one therapeutic agent .
12. A method for inhibiting the transmission of an HIV retrovirus to a cell, which is to contact the cell with an effective amount of DP-178 or a pharmaceutically acceptable derivative thereof and an effective amount of at least one therapeutic agent .
13. The method of claim 9, 10, 11 or 12, wherein the therapeutic agent is an antiviral.
14. The method of claim 13, wherein the antiviral agent is a reverse transcriptase inhibitor, a viral protease inhibitor, a cytokine, a cytokine inhibitor, an inhibitor of glycosylation or an inhibitor of mRNA processes viral.
15. 15. The method of claim 13, wherein the antiviral is a nucleoside analog.
16. 16. The method of claim 15, wherein the nucleoside analogue is AZT, ddI, ddC, ddA, d4T or 3TC.
17. 17. The method of claim 13, wherein the antiviral is interferon-a, interferon-β or interferon- ?.
18. 18. The method of claim 1, 2, 9 or 10 wherein the administration is in sequence.
19. 19. The method of claim 1, 2, 9 or 10, wherein the administration is simultaneous.
20. 20. The method of claim 1, 2, 9 or 10, wherein the administration is oral.
21. 21. The method of claim 1, 2, 9 or 10, wherein the administration is parenteral.
22. 22. The method of claim 21, wherein the administration is intravenous.
23. A pharmaceutically acceptable composition, useful for the treatment of HIV infection, containing an effective amount of DP-178 or a pharmaceutically acceptable derivative thereof, an effective amount of another therapeutic agent and a pharmaceutically acceptable carrier.
24. A pharmaceutical composition, useful for the treatment of HIV infection, containing an effective amount of DP-107 or a pharmaceutically acceptable derivative thereof, an effective amount of another therapeutic agent and a pharmaceutically acceptable carrier.
25. The pharmaceutical composition of claim 23 or 24, wherein the therapeutic agent is an antiviral.
26. The pharmaceutical composition of claim 25, wherein the antiviral agent is a nucleoside analog.
27. The pharmaceutical composition of claim 26, wherein the nucleoside analogue is AZT, ddI, ddC, ddA or 3TC.
28. A method of treating HIV infection to an individual, which consists in (a) administering an effective amount of DP-107, DP-178 or a pharmaceutically acceptable derivative thereof; (b) administering an effective amount of another antiviral; and (c) administering DP-107, DP-178 or a pharmaceutically acceptable derivative thereof.
29. 29. The method of claim 28, wherein the DP-107 or a pharmaceutically acceptable derivative thereof, an effective amount of another therapeutic agent and a pharmaceutically acceptable carrier is administered in step (a) and DP-178 or a pharmaceutically derivative acceptable of this is administered in step (c).
30. 30. The method of claim 29, wherein step (a) to (c) is repeated until the symptoms of the disease are alleviated.
31. 31. A method of treating HIV infection in an individual, consisting of administering an effective amount of a DP-178 like peptide or a pharmaceutically acceptable derivative thereof and an amount of at least one therapeutic agent. .
32. 32. The method of claim 31, wherein the DP-178-like peptide is derived from the simian immunodeficiency virus. The method of claim 32, wherein the DP-178 like peptide is selected from the group consisting of T-391, T-392, T-393, T-394, T-395, T-394, T -395, T-396, T-397, T-398, T-399, 400.