LIPOPEPTÍDEO, POLIPEPTÍDEO, CONJUGADO, ÁCIDO NUCLEICO ISOLADO, VETOR, CÉLULA HOSPEDEIRA, MULTÍMERO, COMPOSIÇÕES, MÉTODO PARA INIBIR A INFUSÃO DE MEMBRANA VIRAL E USO DO LIPOPEPTÍDEO

Abstract

The present disclosure relates to a lipopeptide or a pharmaceutically acceptable salt, solvate, hydrate, complex, chelate, non-covalent complex or a prodrug thereof, which is a broad-spectrum viral membrane fusion inhibitor, can strongly inhibit a human immunodeficiency virus and multiple other viruses, and can be used for treating a human immunodeficiency virus infection, multiple other virus infections, and diseases caused by the infections.

Description

1 / 60 “Lipopeptide, polypeptide, conjugate, isolated nucleic acid, vector, host cell, multimer, composition and use of lipopeptide” TECHNICAL AREA

[001] This disclosure pertains to the field of biomedicine and relates to a lipopeptide (or a salt, solvate, hydrate, complex, chelate, non-covalent complex, or pharmaceutically acceptable prodrug thereof) and also relates to a polypeptide (or a variant thereof). The lipopeptide (or a salt, solvate, hydrate, complex, chelate, non-covalent complex, or pharmaceutically acceptable prodrug thereof) is a broad-spectrum viral membrane fusion inhibitor that can potently inhibit human immunodeficiency virus and several other viruses and therefore can be used to treat human immunodeficiency virus infection, several other viral infections, and diseases caused by infections. Background of the Invention

[002] Infections caused by viruses, such as Human Immunodeficiency Virus (HIV), Novel Coronavirus (SARS-CoV-2), Middle East Respiratory Syndrome Virus (MERS-CoV), Ebola Virus (EBOV), Marburg Virus (MARV), Hepatitis B Virus (HBV), Influenza Virus (IAV), Rabies Virus (RABV), Vesicular Stomatitis Virus (VSV), and Respiratory Syncytial Virus (RSV), seriously endanger human health and social stability. Effective antiviral drugs, especially broad-spectrum antiviral drugs, are in severe global shortage. Membrane fusion, such as the formation of fertilized eggs and the transport and release of intracellular substances, is an extremely important biological phenomenon. Many viruses, including those mentioned above, infect host cells via the fusion pathway of Petition 870250105357, dated 11 / 18 / 2025, pp. 94 / 171 2 / 60 membranes. The development of specific or broad-spectrum antiviral drugs that target common mechanisms of viral membrane fusion has significant scientific and practical value.

[003] HIV infection leads to Acquired Immunodeficiency Syndrome (AIDS). Currently, there are no effective vaccines to prevent HIV nor medications to completely cure HIV infection. Existing anti-HIV medications include reverse transcriptase inhibitors, protease inhibitors, viral entry inhibitors, integrase inhibitors, and similar drugs, and they work by blocking viral replication at different stages and play an important role in the treatment and prevention of AIDS. The widely used highly active antiretroviral therapy ("cocktail" therapy) mainly consists of three to four reverse transcriptase inhibitors and protease inhibitors. However, due to the persistence of HIV infection, it is necessary to administer drugs to patients for a long period of time, easily leading to drug resistance, which seriously affects the effect of clinical treatment.Consequently, the development of new anti-HIV drugs has always been an important demand for the prevention and control of AIDS.

[004] HIV entry into host cells is mediated by the trimeric envelope glycoprotein (Env) on its surface, which includes a surface subunit gp120 and a transmembrane subunit gp41. During the HIV infection process, gp120 first binds to the CD4 receptor and then to the co-receptor (such as CCR5 or CXCR4), which induces conformational changes in gp120, thus exposing gp41 and activating the membrane fusion function of gp41. The N-terminal fusion peptide (FP) of gp41 is first inserted into the membrane of a target cell, then the C-terminal heptal region (CHR) is reverse-linked to the N-terminal heptal region (NHR) to form a stable six-helix bundle (6-HB) structure, thus bringing the membrane Petition 870250105357, dated 11 / 18 / 2025, pp. 95 / 171 3 / 60 viral to near the cell membrane for fusion, to allow HIV genetic material to enter the cell and result in infections. The crystal structure[1] shows that the C-terminal of the NHR helix contains a deep hydrophobic pocket, which has always been recognized as an important target for antiviral drugs, while the “WMEWDREI” sequence at the N-terminal of the CHR helix is ​​an NHR pocket-binding domain (NBP), where eight amino acids are located at positions a, b, c, d, e, f, g and a of the CHR helix, respectively. Among them, the two W (tryptophan) at positions a and I (isoleucine) at position a are hydrophobic amino acids and are inserted into the NHR pocket to mediate extensive hydrophobic effects, which is crucial for the formation and function of the viral fusion protein 6-HB.

[005] Viral membrane fusion inhibitors act in the early stages of viral replication, blocking its entry into target cells and therefore have obvious advantages in both treatment and prevention. However, only one membrane fusion inhibitor has been approved by the US Food and Drug Administration (FDA) for clinical application, the HIV membrane fusion inhibitor enfuvirtide (also known as T20). As shown in Figure 1, T20 is a polypeptide derived from the gp41 CHR and free of the PBD sequence, consisting of 36 amino acids, and exerts its antiviral effect by competitively binding to the NHR to block the formation of the virus's 6-HB. Due to its relatively low activity in inhibiting the virus and its relatively short half-life, T20 needs to be administered in high doses every day (twice daily, 90 mg each time). T20 readily induces drug resistance, rendering clinical treatment ineffective.Therefore, the development of new HIV membrane fusion inhibitors is always a cause for concern both domestically and internationally.

[006] Currently, research and development of HIV membrane fusion inhibitors is primarily focused on the role of PBD, Petition 870250105357, dated 11 / 18 / 2025, pp. 96 / 171 4 / 60 especially in the use of the C34 polypeptide published in the early years as a design template[2]. C34 contains PBD and its amino acid sequence is recognized as the core sequence of CHR. Following T20, the original pharmaceutical companies further designed a second-generation inhibitor T1249 and a third-generation inhibitor T2635[3], both containing the PBD sequence (see Figure 1). Both Sifuvirtide (SFT) and Albuvirtide (ABT), which were initially developed in China, are designed based on the C34 sequence[4][5]. sft is obtained by mutating 14 amino acids of C34 and adding serine (S) and glutamic acid (E) to the N-terminus and C-terminus, respectively, to increase the stability and target binding capacity of the polypeptide.ABT is obtained by mutating only three amino acids of C34 and incorporating 3-maleimidopropanoic acid (MPA) into the lysine (K) side chain at position 13, so that it has the ability to bind to serum albumin. Although the antiviral activities of SFT and ABT are not substantially improved compared to T20 and C34, they have a prolonged biological half-life, so the frequency of administration can be reduced. Modification of the C-terminal of the C34 polypeptide with cholesterol molecules to form a C34-Chol lipopeptide can significantly improve antiviral activity and biological half-life[6].

[007] The present team of inventors has long been involved in the research and development of HIV membrane fusion inhibitors and has designed multiple HIV membrane fusion inhibitors based on CHR polypeptides according to the structure-function relationship of gp41[7]. Among them, LP-11 contains a PBD motif and its C-terminal is modified with palmitic acid molecules; while LP-98 does not contain the PBD motif and its C-terminal is modified with cholesterol. Compared to LP-11, LP-98 showed significantly improved antiviral activity. However, the inventors also discovered that LP-98 has an activity Petition 870250105357, dated 11 / 18 / 2025, pp. 97 / 171 5 / 60 inhibitory activity is significantly reduced against T20-resistant HIV strains, thus affecting their drug delivery capabilities. Therefore, there is a persistent need for research and development of a new viral membrane fusion inhibitor drug to meet clinical needs.

[008] The diagram for the sequence structures of T20, C34, T1249, T2635, SFT, ABT, C34-Chol, LP-11 and LP-98 mentioned above is shown in Figure 1. Brief Description of the Invention

[009] The technical problem to be solved by the present disclosure is how to effectively inhibit HIV and some other viruses with membrane fusion function. The inventors of the present disclosure have long been dedicated to the development of a potent, broad-spectrum, long-acting viral membrane fusion inhibitor. In their research, the inventors surprisingly discovered that, based on the HIV CHR sequence, the introduction of a “rigid linker” and the substitution of some amino acids in the PBD can significantly increase the antiviral activity of the polypeptide.

[0010] Therefore, in one aspect, the present disclosure provides a lipopeptide or a pharmaceutically acceptable salt thereof, the lipopeptide being a viral membrane fusion inhibitor that can inhibit viruses such as HIV, SARS-CoV-2 and mutant strains thereof, MERS-CoV, EBOV, MARV, IAV, RABV and VSV.

[0011] In another aspect, the present disclosure provides a polypeptide or a variant thereof, and a conjugate comprising the polypeptide or the variant thereof.

[0012] In another aspect, the disclosure provides an isolated nucleic acid encoding the polypeptide or variant thereof, a vector comprising the isolated nucleic acid, and a host cell comprising Petition 870250105357, dated 11 / 18 / 2025, pp. 98 / 171 6 / 60 the isolated nucleic acid or the vector.

[0013] In another aspect, the disclosure provides a multimer formed from the lipopeptide or the pharmaceutically acceptable salt thereof or the polypeptide or variant thereof.

[0014] In another aspect, the present disclosure provides a composition comprising the lipopeptide or the pharmaceutically acceptable salt thereof, the polypeptide or a variant thereof, the conjugate, the isolated nucleic acid, the vector, the host cell or the multimer, and a pharmaceutical composition comprising the lipopeptide or the pharmaceutically acceptable salt thereof or the polypeptide or a variant thereof.

[0015] In another aspect, the present disclosure provides for the use of the lipopeptide or a pharmaceutically acceptable salt thereof or of the polypeptide or a variant thereof in the manufacture of a medicament or in the treatment of a disease. Detailed Description of the Invention

[0016] The purposes and implementation of this disclosure will be described in more detail below.

[0017] In the technique for developing a lipopeptide-based viral membrane fusion inhibitor, it is usually necessary to add a linker between a polypeptide sequence and an aliphatic group (e.g., fatty acids and cholesterol, etc.) to act as a linker arm. The expected binding site of the aliphatic groups is a viral membrane or a cell membrane, which makes the polypeptide enriched in a target region, significantly improving the antiviral activity of the polypeptide. Since a polypeptide tends to form a stable secondary structure and possesses strong structural rigidity, a flexible linker is usually selected for the connection between the polypeptide and the aliphatic group, so that the polypeptide and the aliphatic group Petition 870250105357, dated 11 / 18 / 2025, pp. 99 / 171 7 / 60 can form suitable conformations, respectively, and bind to their respective binding sites, and their respective effects are sufficiently exerted, avoiding interaction caused by steric hindrance and other reasons. Common flexible linkers include a combination of glycine (G) and serine (S), for example, (GGGGS)n or (GSGSG)n, where the size of n can be adjusted to increase or decrease the distance between domains. Another common flexible linker is a small molecule of polyethylene glycol (PEG)n, where n is mainly between 2 and 24. Currently, all viral membrane fusion inhibitor lipopeptides reported in the literature use a flexible linker.For example, the HIV membrane fusion inhibitor C34-Chol uses GSG, and LP11 uses PEG8; for another example, the SARS-CoV2 membrane fusion inhibitor IPB02V3 uses PEG8, IPB24 to IPB27 use PEG4, PEG5, PEG6 and PEG8 respectively[8], EKL1C uses GSG[9], EK1C4 uses a tandem of GSGSG and PEG4[8], [SARSHRC-PEG4]2-chol uses PEG4

[10] , etc.

[0018] The (EAAAK)n sequence, capable of forming an alpha helix, is a common rigid ligand for the preparation of fusion proteins. It possesses an internal hydrogen bond and comes into close contact with the main structure of the peptide chain, and is rigid and stable, thus effectively separating the domains. However, there is no precedent for currently prepared lipopeptide HIV membrane fusion inhibitors utilizing a rigid ligand. This disclosure prepares a lipopeptide using the EAAAK rigid ligand sequence, and surprisingly, the rigid ligand was found to confer a significant helical structure and potent antiviral activity to the polypeptide.In a specific example from this disclosure, using a C34 polypeptide as a design model, lipopeptides C34-LP1 and C34-LP2 were first prepared using a flexible GSGSG ligand and a rigid EAAAK ligand, respectively, and the results show that the rigid EAAAK ligand helps to improve the anti-HIV activity of the lipopeptide. Furthermore, Petition 870250105357, dated 11 / 18 / 2025, pp. 100 / 171 8 / 60 Three new lipopeptides LP-121, LP-122, and LP-123, using EAAAK as a ligand, were designed and, at the corresponding b, c, f, and g positions of the CHR helix, amino acid pairs EE and KK were introduced to promote the formation of a "salt bridge" structure at the i+4 positions. Experiments unexpectedly demonstrated that the lipopeptide LP-123, containing a shorter sequence, exhibits ideal anti-HIV activity.

[0019] The amino acid WMEWDREI at the N-terminal end of the CHR helix in gp41 is a pocket-binding domain (PBD), where the two W at the a and b positions of the CHR helix and the I at the a position are inserted into the NHR pocket to mediate extensive hydrophobic effects, which play an important role in the formation of the 6-HB fusion protein. Therefore, research and development of next-generation HIV membrane fusion inhibitors focuses primarily on the effects of the PBD, especially using a C34 polypeptide containing PBD as a design template. Representative inhibitors in this field include T1249, T2635, SFT, ABT, and C34-Chol, etc. Although amino acid substitution is a common strategy to optimize polypeptide inhibitors, for HIV membrane fusion inhibitors, as currently reported in the literature, the two W in the PBD sequence are used without exception, and there is no precedent for the substitution of W with other amino acids.To further improve the antiviral activity of the inhibitors, surprisingly, the present disclosure demonstrates that replacing the two hydrophobic W molecules in the PBD with two hydrophilic and tyrosine (Y) molecules of small molecular weight can significantly improve the antiviral activity of HIV membrane fusion inhibitors. In the specific implementation process, LP-124 and LP-125 are prepared using the lipopeptides LP-122 and LP-123 mentioned above as templates, respectively, and, based on experiments, it is found that replacing W with Y can significantly improve the antiviral activity of the inhibitors. Such a technical strategy alters... Petition 870250105357, dated 11 / 18 / 2025, pp. 101 / 171 9 / 60 The interaction between the PBD and the NHR pocket changes from a hydrophobic to a hydrophilic interaction, offering a novel approach for the development of HIV membrane fusion inhibitors in the field.

[0020] Furthermore, the present disclosure, based on LP-125, prepares the lipopeptide LP-126 by replacing the first amino acid T at the N-terminal with a negatively charged amino acid E, to further increase the hydrophilic interaction and stability of the lipopeptide's N-terminal. Additionally, the lipopeptide LP-127 is prepared by reducing the amino acid at the α-position of LP-126 to E and replacing I at the α-position with the amino acid L (leucine), which has relatively low hydrophilicity; and LP-128, containing only one Y, is prepared by removing three amino acids at the N-terminal end of LP-127. These new inhibitors share the common characteristics of containing an EAAAK ligand, a PBD motif with W replaced by Y, and EE-KK salt-rich bridge-forming amino acids. In terms of amino acid sequence, only 8 amino acids retain the amino acids from the original CHR sequence.Through specific experiments, these new inhibitors were found to possess potent anti-HIV activity. More unexpectedly, LP-127 and LP-128 were found to effectively inhibit infections from pseudoviruses such as SARS-CoV-2, MERS-CoV, EBOV, MARV, IAV, and RABV, reflecting their broad-spectrum antiviral activity.

[0021] The sequence structure diagrams of LP-121, LP-122, LP-123, LP-124, LP-125, LP-126, LP-127, and LP-128 above are shown in Figure 2. In the lipopeptide structural formulas shown in Figure 2, Ac represents an acetyl group, which is an amino-terminal protecting group of the polypeptide, and Chol represents a cholesterol molecule to modify the C-terminal of the polypeptide, and the modification occurs in the amino acid K side chain at the C-terminal of the polypeptide. NH2 represents an amino group, which is a carboxyl-terminal protecting group of the polypeptide. Petition 870250105357, dated 11 / 18 / 2025, pp. 102 / 171 10 / 60

[0022] The present disclosure is based, at least in part, on the inventors' unexpected discovery described above. Thus, in one aspect, the present disclosure provides a lipopeptide or a salt, a solvate, a hydrate, a complex, a chelate, a non-covalent complex or a pharmaceutically acceptable prodrug thereof, comprising a polypeptide or a variant thereof and a modification group linked to the C-terminal of the polypeptide or variant thereof by means of a linker and, optionally, a terminal protecting group of the polypeptide: (X1X2X3)mX4X5X6X7X8X9X10X11X12X13X14X15IX16X17LX18X19X20X21 X22X23QQX24X2 5N(EX26)n Formula I where the polypeptide is represented by Formula I; the modifying group is a lipophilic compound; the linker is -(EAAAK)m-, -(XP)n2-, (EAAAK)n1-X27- or -(XP)n2-X27-, X1 is T, E, or S; X2 is W or a hydrophilic amino acid; X3 is E, M, or Q; m is O or I; X4 is E, A, or T; X5 is W or a hydrophilic amino acid; X6 is E or D; X7 is R, K, or Q; X8 is E, K, or A; X9 is L or I; Xw is E, N, or A; X11 is E or N; X12 is L or Y; X13 is E, T, or A; Xu is K, S, R, or A; X15 is K, L, R, or Q; X16 is E, H, T, or Y; X17 is E, S, R, or A; X18 is L or I; Xw is K, E, or R; X20 is K, E, Q, or A; X21 is A or S; X22 is E or Q; X23 is E, N, or I; X24 is K, E, or D; X25 is K or R; X26 is Q, E, R, A, or Y; n is 0 or 1; X is any amino acid; X27 is K or C; m is a natural number between 1 and 5; n2 is a natural number between 1 and 5, and the variant differs from the polypeptide from which the variant is derived only in the substitution (e.g., a conservative or non-conservative substitution) of one or more (such as 1, 2, 3, 4, or 5) amino acid residues, and retains the biological function of the polypeptide from which the variant is derived.

[0023] In some embodiments, X1 is T or E. In some Petition 870250105357, dated 11 / 18 / 2025, pp. 103 / 171 In 11 / 60 embodiments, Xi is T. In some embodiments, Xi is E.

[0024] In some embodiments, X2 is W, D, E, H, K, Q, R, S, T or Y. In some embodiments, X2 is W or Y. In some embodiments, X2 is Y. In some embodiments, X2 is W.

[0025] In some embodiments, X3 is E or M. In some embodiments, X3 is E. In some embodiments, X3 is M.

[0026] In some embodiments, X4 is E.

[0027] In some embodiments, X5 is W, D, E, H, K, Q, R, S, T or Y. In some embodiments, X5 is W or Y. In some embodiments, X5 is Y. In some embodiments, X5 is W.

[0028] In some embodiments, X6 is E.

[0029] In some embodiments, X7 is R or K. In some embodiments, X7 is R. In some embodiments, X7 is K.

[0030] In some embodiments, X8 is E or K. In some embodiments, X8 is E. In some embodiments, X8 is K.

[0031] In some embodiments, Xioé E or N. In some embodiments, Xioé E. In some embodiments, Xioé N.

[0032] In some embodiments, Xii is E.

[0033] In some embodiments, Xi2é L.

[0034] In some embodiments, Xi3 is E or T. In some embodiments, Xi3 is E. In some embodiments, Xi3 is T.

[0035] In some embodiments, Xi4 is K or S. In some embodiments, Xi4 is K. In some embodiments, Xi4 is S.

[0036] In some embodiments, Xi5 is K or L. In some embodiments, Xi5 is K. In some embodiments, Xi5 is L.

[0037] In some embodiments, Xi6é E or H. In some embodiments, Xi6é E. In some embodiments, Xi6é H.

[0038] In some embodiments, Xi7é E or S. In some Petition 870250105357, dated 11 / 18 / 2025, pp. 104 / 171 12 / 60 embodiments, Xi7é E. In some embodiments, Xi7é S.

[0039] In some embodiments, Xwé L.

[0040] In some embodiments, Xwé K or E. In some embodiments, Xwé K. In some embodiments, Xwé E.

[0041] In some embodiments, X20 is K or E. In some embodiments, X20 is K. In some embodiments, X20 is E.

[0042] In some embodiments, X21 is A.

[0043] In some embodiments, X22 is E.

[0044] In some embodiments, X23 is E or N. In some embodiments, X23 is E. In some embodiments, X23 is N.

[0045] In some embodiments, X24 is K or E. In some embodiments, X24 is K. In some embodiments, X24 is E.

[0046] In some embodiments, X25 is K.

[0047] In some embodiments, X26 is Q.

[0048] In some embodiments, X is A, K, or E.

[0049] In some embodiments, m is 0. In some embodiments, m is 1.

[0050] In some embodiments, n is 0. In some embodiments, n is 1.

[0051] In some embodiments, X27 is K. In some embodiments, X27 is C.

[0052] In some embodiments, m is a natural number between 1 and 4. In some embodiments, ni is a natural number between 1 and 3. In some embodiments, m is 1 or 2. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3. In some embodiments, m is 4. In some embodiments, m is 5.

[0053] In some embodiments, n2 is a natural number. Petition 870250105357, dated 11 / 18 / 2025, pp. 105 / 171 13 / 60 between 1 and 4. In some embodiments, n2 is a natural number between 1 and 3. In some embodiments, Ϡ2 is 1 or 2. In some embodiments, n2 is 1. In some embodiments, n2 is 2. In some embodiments, n2 is 3. In some embodiments, n2 is 4. In some embodiments, n2 is 5.

[0054] In some embodiments, X25 is K, and the polypeptide is represented by Formula II, (X1X2X3)mX4X5X6X7X8X9X10X11X12X13X14X15IX16X17LX18X19X20X21 X22X23QQX24K N(EX26)n Formula II, in which the definitions of X1, X2, X3, m, X4, X5, X6, X7, X8, X9, X10, X11, X12, X13, X14, X15, X16, X17, X18, X19, X20, X21, X22, X23, X24, X26 and Π are as described in any embodiment according to this disclosure.

[0055] In some embodiments, X4 is E, X25 is K and the polypeptide is represented by Formula III, (X1X2X3)mEX5X6X7X8X9X10X11X12X13X14X15IX16X17LX18X19X20X21X22X23QQX24KN(EX26)n Formula III wherein, the definitions of X1, X2, X3, m, X5, X6, X7, X8, X9, X10, X11, X12, X13, X14, X15, X16, X17, X18, Xi9, X20, X21, X22, X23, X24, X26 and Π are as described in any embodiment according to the present disclosure.

[0056] In some embodiments, X4 is E, X10 is E, X11 is E, X12 is L, X13 is E, X14 is K, X15 is K, X16 is E, X17 is E, X18 is L, X19 is K, X20 is K, X21 is A, X22 is E, X23 is E, X24 is K, X25 is K, and the polypeptide is represented by Formula IV, (X1X2X3)m-EX5X6X7X8X9EELEKKIEELLKKAEEQQKKN(EX26)n Formula IV Petition 870250105357, dated 11 / 18 / 2025, pp. 106 / 171 14 / 60

[0057] Wherein, the definitions of Xi, X2, X3, m, X5, Xe, X7, Xs, X9, X26 and are as described in any embodiment in accordance with the present disclosure.

[0058] In some embodiments, X4 is E, Xe is E, X7 is K, X10 is E, X11 is E, X12 is L, X13 is E, X14 is K, X15 is K, Xi6 is E, X17 is E, Xis is L, X19 is K, X2o is K, X21 is A, X22 is E, X23 is E, X24 is K, X25 is K, and the polypeptide is represented by Formula V, (X1X2X3)m-EX5EKXsX9EELEKKIEELLKKAEEQQKKN(EX26)n Formula V.

[0059] Wherein, the definitions of X1, X2, X3, m, X5, Xs, X9, X26 and n are as described in any embodiment in accordance with this disclosure.

[0060] In some embodiments, the terminal protecting group of the polypeptide comprises an N-terminal (amino-terminal) protecting group and / or a C-terminal (carboxy-terminal) protecting group. In some embodiments, the lipopeptide, according to the present disclosure, comprises an N-terminal protecting group and a C-terminal protecting group. As is well known, the N-terminal protecting group can be any one selected from the group consisting of acetyl (Ac), amino (NH2), maleoyl, succinyl, tert-butoxycarbonyl, benzyloxy, another hydrophobic group and a macromolecular carrier group. As is well known, the C-terminal protecting group can be any one selected from the group consisting of amino (NH2), carboxyl, hydroxyl, amido, tert-butoxycarbonyl, another hydrophobic and macromolecular carrier group. In some embodiments, the N-terminal protecting group is acetyl (Ac). In some embodiments, the C-terminal protecting group is amino (NH2).

[0061] The amino acid abbreviations in the polypeptide according to the present disclosure have the meanings well known in the art, by Petition 870250105357, dated 11 / 18 / 2025, pp. 107 / 171 15 / 60 example: W is tryptophan, M is methionine, E is glutamic acid, D is aspartic acid, R is arginine, I is isoleucine, N is asparagine, Y is tyrosine, T is threonine, S is serine, L is leucine, H is histidine, Q is glutamine, K is lysine, A is alanine, G is glycine, and the like. In some embodiments, the amino acids are L-configured amino acids, and one or more (e.g., 2-5, 2-4, or 2-3) amino acid residues in the polypeptide may also be replaced by amino acids with chemically similar properties, such as L-configured amino acids, D-configured amino acids, artificially modified amino acids, or rare amino acids found in nature, to improve the bioavailability, stability, and / or antiviral activity of the polypeptide, wherein the D-configured amino acid refers to an amino acid corresponding to an L-configured amino acid that constitutes a protein;An artificially modified amino acid refers to a common L-shaped amino acid that constitutes a protein and is modified by methylation, phosphorylation, or similar means; and a rare amino acid found in nature includes both an uncommon amino acid that constitutes a protein and an amino acid that does not constitute a protein, for example, 5-hydroxylysine, methylhistidine, gamma-aminobutyric acid, and homoserine.

[0062] In some embodiments, the lipophilic compound is cholesterol (Chol), fatty acid, dihydrosphingosine (DHS) or vitamin E (tocopherol, Toc), etc. In some embodiments, cholesterol includes: cholesteryl hemisuccinate, 2-cholesteryl acetic acid, 2-cholesteryl propionic acid, 3-cholesteryl propionic acid, 2-cholesteryl butyric acid, 2-cholesteryl isobutyric acid, 3-cholesteryl butyric acid, 3-cholesteryl isobutyric acid, 4-cholesteryl butyric acid, 2-cholesteryl valeric acid, 2-cholesteryl isovaleric acid, 3-cholesteryl valeric acid, 5-cholesteryl valeric acid, 2-cholesteryl caproic acid, 6-cholesteryl caproic acid, 2-cholesteryl enanthic acid, 7-cholesteryl enanthic acid, 2-cholesteryl caprylic acid, 8-cholesteryl caprylic acid, cholesteryl bromoacetate, etc. In some embodiments, fatty acid includes a fatty acid containing Petition 870250105357, dated 11 / 18 / 2025, pp. 108 / 171 16 / 60 containing 8 to 20 carbon atoms, for example, octadecanoic acid or palmitic acid.

[0063] In some embodiments, the lipophilic compound is cholesterol (Chol). In some embodiments, the lipophilic compound is a fatty acid. In some embodiments, the lipophilic compound is dihydrosphingosine (DHS). In some embodiments, the lipophilic compound is vitamin E (tocopherol, Toc). In some embodiments, the cholesterol is cholesteryl hemisuccinate. In some embodiments, the lipophilic compound is 2-cholesteryl acetic acid. In some embodiments, the lipophilic compound is 2-cholesteryl propionic acid. In some embodiments, the lipophilic compound is 3-cholesteryl propionic acid. In some embodiments, the lipophilic compound is 2-cholesteryl butyric acid. In some embodiments, the lipophilic compound is 2-cholesteryl isobutyric acid. In some embodiments, the lipophilic compound is 3-cholesteryl butyric acid.In some embodiments, the lipophilic compound is 3-cholestylerisobutyric acid. In some embodiments, the lipophilic compound is 4-cholestylerbutyric acid. In some embodiments, the lipophilic compound is 2-cholestylervaleric acid. In some embodiments, the lipophilic compound is 2-cholestylerisovaleric acid. In some embodiments, the lipophilic compound is 3-cholestylervaleric acid. In some embodiments, the lipophilic compound is 5-cholestylervaleric acid. In some embodiments, the lipophilic compound is 2-cholestylercaproic acid. In some embodiments, the lipophilic compound is 6-cholestylercaproic acid. In some embodiments, the lipophilic compound is 2-cholestylerenanthic acid. In some embodiments, the lipophilic compound is 7-cholestylerenanthic acid. In some embodiments, the lipophilic compound is 2-cholesterylcaprylic acid.In some embodiments, the lipophilic compound is 8-cholesterylcaprylic acid. In some... Petition 870250105357, dated 11 / 18 / 2025, pp. 109 / 171 In 17 / 60 embodiments, the lipophilic compound is cholesteryl bromoacetate. In some embodiments, the fatty acid is a fatty acid containing 8 to 20 carbon atoms. In some embodiments, the lipophilic compound is octadecanoic acid. In some embodiments, the lipophilic compound is palmitic acid.

[0064] In some embodiments, the linker is -(EAAAK)ni-, where the definition of ni is as described in any embodiment according to this disclosure. In some embodiments, the linker is -(XP)n2-, where the definitions of X and n2 are as described in any embodiment according to this disclosure. In some embodiments, the linker is -(EAAAK)ni-X27-, where the definitions of n2 and X27 are as described in any embodiment according to this disclosure. In some embodiments, the linker is -(XP)n 2-X27-, where the definitions of X, n2 and X27 are as described in any embodiment according to this disclosure.

[0065] The lipophilic compound may be linked to the side chain of the terminal amino acid of the ligand or directly linked to the ligand. Among them, fatty acid, dihydrosphingosine, and vitamin E can modify the polypeptide by performing an amidation reaction with the amino group of the lysine side chain (Lys) in the ligand; cholesterol can modify the polypeptide by performing an amidation reaction with the amino group of the lysine side chain (Lys) in the ligand or by performing a thioether formation reaction with the sulfhydryl group of the cysteine ​​side chain (Cys) in the ligand. In some specific embodiments, cholesterol is cholesterol hemisuccinate, which modifies the polypeptide by performing an amidation reaction with the amino group of the K side chain in the ligand. It is well known in the art that cholesteryl bromoacetate, as a polypeptide modification group, can also achieve polypeptide modification by performing a thioether formation reaction with Petition 870250105357, dated 11 / 18 / 2025, pp. 110 / 171 18 / 60 the sulfhydryl group of the cysteine ​​side chain (C) in the ligand.

[0066] In some embodiments, the lipopeptide has an amino acid sequence selected from amino acid sequences as set forth in SEQ ID NO: 11-19.

[0067] As is well known in the art, the chemical modification of a polypeptide by the use of lipids, to obtain so-called “lipopeptides”, can increase the ability to reach the cell membrane and the antiviral activity of the polypeptide and, at the same time, significantly improve the stability and biological half-life of the polypeptide. Therefore, as is also known in the art, the polypeptide according to the present disclosure also possesses antiviral activity similar to that of the lipopeptide. Based on this, in another aspect, the present disclosure further provides a polypeptide or a variant thereof, which is the polypeptide or variant thereof as described in any of the embodiments described above, according to the present disclosure. Specifically, the polypeptide comprises or consists of a sequence represented by Formula I, Formula II, Formula III, Formula IV or Formula V: (X1X2X3)mX4X5X6X7X8X9X10X11X12X13X14X15IX16X17LX18X19X20X21 X22X23QQX24X2 5N(EX26)n Formula I, (X1X2X3)mX4X5X6X7X8X9X10X11X12X13X14X15IX16X17LX18X19X20X21 X22X23QQX24K N(EX26)n Formula II, (X1X2X3)mEX5X6X7X8X9X10X11X12X13X14X15IX16X17LX18X19X20X21X22X23QQX24KN(EX26)n Formula III, (X1X2X3)m-EX5X6X7X8X9EELEKKIEELLKKAEEQQKKN(EX26)n Formula IV, Petition 870250105357, dated 11 / 18 / 2025, pp. 111 / 171 19 / 60 (XiX2X3)m-EX5EKX8X9EELEKKIEELLKKAEEQQKKN(EX26)n Formula V, in which, the definitions of Xi, X11, X12, X13, X14, X15, X16, X17, X18, X19, X20, X21, X22, X23, X24, X25, X26 and π are as described in any embodiment according to this disclosure.

[0068] In some embodiments, the lipopeptide has an amino acid sequence selected from amino acid sequences as set forth in SEQ ID NO: 21-29.

[0069] As is well known in the art, the amino acids corresponding to the aed positions of the CHR helix are essential amino acids for the formation of the 6-HB structure by the binding of CHR to the target sequence NHR, and are conservative in sequence and function, so they are not easily substituted by other amino acids. In contrast, the amino acids corresponding to the b, c, f, and g positions of the CHR helix have little or no direct interaction with NHR and, therefore, are easily substituted by other amino acids without affecting or with only a slight effect on the antiviral activity of the polypeptide. Thus, the amino acids in the polypeptide can undergo substitution, addition, or deletion of one or more other amino acids, and the polypeptide still has the activity of inhibiting HIV and / or other viruses.Amino acid substitution refers to the replacement of an amino acid residue at a position in the polypeptide sequence by another amino acid, preferably a conservative amino acid, i.e., a conservative substitution; amino acid addition refers to the insertion of additional amino acid residue(s) at the N-terminus or C-terminus or another appropriate position in the polypeptide sequence, and the inserted amino acid residues may be totally or partially contiguous, or non-contiguous to each other; amino acid deletion refers to the removal of one or more amino acid residues from the sequence. Petition 870250105357, dated 11 / 18 / 2025, pp. 112 / 171 20 / 60 polypeptide, provided that the modified polypeptide has activity to inhibit viruses.

[0070] The so-called “amino acid conservation” or “amino acid conservation” has well-known meanings in the art. For example, amino acids are classified into acidic amino acids, basic amino acids, and neutral amino acids according to the number of amino groups and carboxyl groups contained in the amino acid molecules, where acidic amino acids refer to E and D, basic amino acids refer to K, R, and H (histidine), and neutral amino acids refer to A, L, I, V, C, Y, G, M, S, T, F (phenylalanine), W, and P (proline). For another example, amino acids are classified into hydrophilic amino acids (D, E, H, K, Q, R, S, T, Y) and hydrophobic amino acids (A, F, I, L, M, P, V, W) according to their hydrophilicity and hydrophobicity.For another example, uncharged hydrophilic amino acids refer to N, Q, S, and T; uncharged aliphatic amino acids refer to A, L, I, V, and G; uncharged nonpolar amino acids refer to C, M, and P; aromatic amino acids refer to Y, F, and W. For another example, amino acids containing an alcohol group include S and T; aliphatic amino acids include L, I, V, and M; cycloalkenyl-related amino acids include F, H, W, and Y. These amino acids with similar sizes, shapes, charges, and chemical properties, including the ability to form covalent or hydrogen bonds, are generally considered conservative amino acids.

[0071] In this disclosure, the term “conservative substitution” refers to amino acid substitutions that would not affect or adversely alter the essential properties of a protein / polypeptide comprising the amino acid sequence. For example, a conservative substitution can be introduced by standard techniques known in the art, such as site-directed mutagenesis and PCR-mediated mutagenesis. Conservative amino acid substitutions include substitutions in which a residue of Petition 870250105357, dated 11 / 18 / 2025, pp. 113 / 171 21 / 60 amino acid is replaced by another amino acid residue with a similar side chain, for example, a residue that is physically or functionally similar (such as, for example, in size, shape, charge, chemical property, including the ability to form covalent bonds or hydrogen bonds, etc.) to the corresponding amino acid residue. Families of amino acid residues with similar side chains have been defined in the art.These families include amino acids with basic side chains (e.g., lysine, arginine, and histidine), amino acids with acidic side chains (e.g., aspartic acid and glutamic acid), amino acids with uncharged polar side chains (e.g., glycine, asparagine, glutamine, serine, threonine, tyrosine, cysteine, and tryptophan), amino acids with nonpolar side chains (e.g., alanine, valine, leucine, isoleucine, proline, phenylalanine, and methionine), amino acids with β-branched side chains (such as threonine, valine, and isoleucine), and amino acids with aromatic side chains (e.g., tyrosine, phenylalanine, tryptophan, and histidine). Therefore, a conservative substitution generally refers to the replacement of a corresponding amino acid residue by another amino acid residue from the same side chain family. Methods for identifying conservative amino acid substitutions are well known in the art.

[0072] The present team of inventors has demonstrated, with over ten years of research experience, that polypeptides derived from substitutions, additions, or deletions of amino acids in an original polypeptide with a sequence identity of up to approximately 30%, 40%, 50%, 60%, 70%, 80%, or 90% as inhibitors, can still have potent antiviral activity. For example, for the lipopeptides LP-126, LP-127, and LP-128 described above, only 8 amino acids from the original CHR prototype are retained, and LP-126 and LP-127 have a sequence identity of only 26.7% with the amino acids of the original CHR prototype, and LP-128 has a sequence identity of 29.6%. Petition 870250105357, dated 11 / 18 / 2025, pp. 114 / 171 22 / 60 with the amino acids of the original CHR prototype. Thus, any of the polypeptides is a polypeptide with a sequence identity of approximately 27%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 93%, 94%, 95%, 96%, 97%, 98% or 99% and having antiviral activity.

[0073] For common rigid ligands used in the preparation of fusion proteins, in addition to the (EAAAK)m sequence capable of forming an alpha helix, another common type of rigid ligand is a proline-rich (P) sequence (XP)n2, where X can be any amino acid, preferably alanine, lysine, or glutamic acid. The (XP)n2 sequence does not have a helical structure, but proline can increase the rigidity of the main structure and effectively separate domains. Thus, in the present disclosure, the (EAAAK)m ligand can also be replaced by the (XP)n2 ligand without significantly affecting the antiviral activity. Therefore, the ligand according to the present disclosure can be (EAAAK)m or (XP)n2. Furthermore, to bind to a lipophilic compound, the ligand can also comprise one or more lysines (K) or cysteines (C).

[0074] The lipopeptides described in this disclosure may contain one or more chiral centers and / or double bonds and similar structures and, therefore, may exist as stereoisomers, including double-bond isomers (e.g., geometric isomers), enantiomers (optical isomerides), or diastereomers. Consequently, any chemical structures within the scope described herein, containing partially or wholly the above-mentioned similar structures, include all possible enantiomers and diastereomers of the lipopeptides, including any pure stereoisomer (e.g., pure geometric isomers, pure enantiomers, or pure diastereomers) and any mixture of these stereoisomers. A person skilled in the art, using separation techniques or asymmetric synthesis methods, may also decompose mixtures of these racemates and stereoisomers into the enantiomers or stereoisomers of their constituents. Lipopeptides include, among others, Petition 870250105357, dated 11 / 18 / 2025, pp. 115 / 171 23 / 60 various optical isomers, racemates and / or other mixtures. In the case above, a single enantiomer or diastereomer, for example, an optically active isomer, can be obtained by an asymmetric synthesis method or a racemate resolution method. Racemate resolution can be performed in several ways, for example, routine recrystallization with auxiliary resolving reagents or chromatography. In addition, lipopeptides also include cis and / or trans isomers with double bonds.

[0075] The lipopeptides of this disclosure include, among others, all the various pharmaceutically acceptable forms of lipopeptides. These pharmaceutically acceptable forms include various salts, solvates, hydrates, complexes, chelates, non-covalent complexes, prodrugs based on the above substances and any mixtures of the above forms.

[0076] The pharmaceutically acceptable salts of this disclosure include acetate, lactobionate, benzenesulfonate, laurate, benzoate, malate, bicarbonate, maleate, bisulfate, mandelate, bitartrate, mesylate, borate, methylbromide, bromide, methylnitrate, calcium edetate, methylsulfate, camsylate, mucate, carbonate, napsylate, chloride, nitrate, clavulanate, N-methylglucamine, citrate, ammonium salt, dihydrochloride, oleate, edetate, oxalate, edisylate, pamoate, embonate, estolate, palmitate, esilate, pantothenate, fumarate, phosphate / diphosphate, gluceptate, polygalacturonate, gluconate, salicylate, glutamate, stearate, glycolylarsanilate, sulfate, hydroxybenzoate, subacetate, hydrabamine, succinate, hydrobromide, tannate, hydrochloride, tartrate, hydroxynaphthoate, theoaclate, iodide, tosylate, triethiodide, lactate and valerate, etc.Depending on the use, a pharmaceutically acceptable salt can be formed from cations such as sodium, potassium, and bismuth, or it can be formed from a base such as ammonia, ethylenediamine, N-methylglutamine, lysine, arginine, ornithine, choline, N,N'-dibenzylethylenediamine, chloroprocaine, diethanolamine, procaine, diethylamine, piperazine. Petition 870250105357, dated 11 / 18 / 2025, pp. 116 / 171 24 / 60 tris(hydroxymethyl)aminomethane and tetramethylammonium hydroxide. These salts can be prepared by conventional methods, for example, by the reaction of a free acid with an organic or inorganic base. In the presence of a basic group (e.g., an amino group), an acid salt, such as a hydrochloride, a hydrobromide, an acetate, and a pamoate, can be used as a drug form; in the presence of an acid group or an alcohol group, a pharmaceutically acceptable ester, such as an acetate, a maleate, and a pivaloyloxymethyl, and an ester known in the literature to improve solubility and hydrolyzability, can be used as a sustained-release drug or prodrug form.

[0077] In another aspect, the present disclosure also provides an isolated nucleic acid that encodes the polypeptide described above or a variant thereof.

[0078] In another aspect, the present disclosure also provides a vector comprising the isolated nucleic acid. Useful vectors for inserting a polynucleotide of interest are well known in the art and include, among others, cloning vectors and expression vectors. In one embodiment, the vector is, for example, a plasmid, cosmid, phage, etc.

[0079] In another aspect, the present disclosure also provides a host cell comprising the isolated nucleic acid described above or the vector described above. Such host cells include, but are not limited to, prokaryotic cells, such as E. coli cells, and eukaryotic cells, such as yeast cells, insect cells, plant cells, and animal cells (e.g., mammalian cells, such as mouse cells and human cells). The host cell of the present disclosure may also be a cell line.

[0080] In another aspect, the present disclosure also provides a multimer formed from the lipopeptide described above, a salt, a solvate, Petition 870250105357, dated 11 / 18 / 2025, pp. 117 / 171 25 / 60 a hydrate, a complex, a chelate, a non-covalent complex or a pharmaceutically acceptable prodrug thereof, or the polypeptide described above or a variant thereof.

[0081] In another aspect, the present disclosure also provides a conjugate comprising the polypeptide described above or a variant thereof and a modification group. In some embodiments, the modification group is attached to the N-terminal or C-terminal of the polypeptide or variant thereof, optionally by means of a linker. In some embodiments, the modification group is a terminal protecting group. The terminal protecting group of the polypeptide comprises an N-terminal protecting group and / or a C-terminal protecting group. As is well known, the N-terminal protecting group can be any one selected from the group consisting of acetyl (Ac), amino (NH2), maleoyl, succinyl, tert-butoxycarbonyl, benzyloxy, another hydrophobic group and a macromolecular carrier group.As is well known, the C-terminal protecting group can be any one selected from the group consisting of amino (NH2), carboxyl, hydroxyl, amide, tert-butoxycarbonyl, other hydrophobic and macromolecular carrier groups.

[0082] In another aspect, the present disclosure also provides a composition comprising the lipopeptide described above, a salt, a solvate, a hydrate, a complex, a chelate, a non-covalent complex or a pharmaceutically acceptable prodrug thereof, or the polypeptide described above or a variant thereof, or the conjugate described above, or the isolated nucleic acid described above, or the vector described above, or the host cell described above, or the multimer described above.

[0083] In another aspect, the present disclosure also provides a pharmaceutical composition comprising the lipopeptide described above, a salt, a solvate, a hydrate, a complex, a chelate, a non-covalent complex or a pharmaceutically acceptable prodrug thereof, and, Petition 870250105357, dated 11 / 18 / 2025, pp. 118 / 171 26 / 60 optionally, further comprising a pharmaceutically acceptable vehicle and / or excipient. In some embodiments, the lipopeptide, a salt, a solvate, a hydrate, a complex, a chelate, a non-covalent complex or a pharmaceutically acceptable prodrug thereof is present in an amount effective to treat a viral infection or a disease caused by viral infection.

[0084] In another aspect, the present disclosure also provides a pharmaceutical composition comprising the polypeptide described above or a variant thereof, optionally further comprising a pharmaceutically acceptable vehicle and / or excipient. In some embodiments, the polypeptide or variant thereof is present in an amount effective for treating a viral infection or a disease caused by viral infection.

[0085] In some embodiments, viral infection is an infection caused by a virus selected from the group consisting of HIV and a drug-resistant strain thereof, SARS-CoV-2 and a mutant strain thereof, MERS-CoV, EBOV, MARV, IAV, RABV, and VSV.

[0086] In some embodiments, the viral infection is an infection caused by HIV or a drug-resistant strain of the same.

[0087] In another aspect, the present disclosure also provides a method for treating a viral infection or a disease caused by viral infection, comprising administering an effective amount of the lipopeptide described above or of a salt, a solvate, a hydrate, a complex, a chelate, a non-covalent complex or a pharmaceutically acceptable prodrug thereof, or of the polypeptide described above or a variant thereof, or of the pharmaceutical composition described above, to an individual in need thereof. In another aspect, the present disclosure also provides a method for inhibiting viral membrane fusion, comprising administering an effective amount of the lipopeptide described above or of a salt, a solvate, a Petition 870250105357, dated 11 / 18 / 2025, pp. 119 / 171 27 / 60 hydrate, a complex, a chelate, a non-covalent complex or a pharmaceutically acceptable prodrug thereof, or of the polypeptide described above or of a variant thereof, or of the pharmaceutical composition described above, for an individual in need thereof. In some embodiments, the viral infection is an infection caused by a virus selected from the group consisting of HIV and a drug-resistant strain thereof, SARS-CoV-2 and a mutant strain thereof, MERS-CoV, EBOV, MARV, IAV, RABV and VSV. In some embodiments, the viral infection is an infection caused by HIV or a drug-resistant strain thereof.

[0088] In another aspect, the present disclosure also provides for the use of the lipopeptide described above or of a salt, a solvate, a hydrate, a complex, a chelate, a non-covalent complex or a pharmaceutically acceptable prodrug thereof, or of the polypeptide described above or a variant thereof, in the manufacture of a pharmaceutical composition, wherein the pharmaceutical composition is used as a viral membrane fusion inhibitor or to treat a viral infection or a disease caused by viral infection. In some embodiments, the viral infection is an infection caused by a virus selected from the group consisting of HIV and a drug-resistant strain thereof, SARS-CoV-2 and a mutant strain thereof, MERS-CoV, EBOV, MARV, IAV, RABV and VSV. In some embodiments, the viral infection is an infection caused by HIV or a drug-resistant strain thereof.

[0089] In another aspect, the present disclosure also provides for the use of the lipopeptide described above or of a salt, solvate, hydrate, complex, chelate, non-covalent complex or pharmaceutically acceptable prodrug thereof, or of the polypeptide described above or a variant thereof, for use as a viral membrane fusion inhibitor or for use in the treatment of a viral infection or disease caused by Petition 870250105357, dated 11 / 18 / 2025, pp. 120 / 171 28 / 60 viral infection. In another aspect, the present disclosure also provides for the use of the polypeptide described above or a variant thereof, for use as a viral membrane fusion inhibitor or for use in the treatment of a viral infection or a disease caused by a viral infection. In some embodiments, the viral infection is an infection caused by a virus selected from the group consisting of HIV and a drug-resistant strain thereof, SARS-CoV2 and a mutant strain thereof, MERS-CoV, EBOV, MARV, IAV, RABV and VSV. In some embodiments, the viral infection is an infection caused by HIV or a drug-resistant strain thereof.

[0090] In another aspect, the present disclosure also provides a pharmaceutical composition for inhibiting viral membrane fusion or a pharmaceutical composition for treating a viral infection or a disease caused by viral infection, comprising the lipopeptide described above or a salt, a solvate, a hydrate, a complex, a chelate, a non-covalent complex or a pharmaceutically acceptable prodrug thereof, or the polypeptide described above or a variant thereof. In some embodiments, the viral infection is an infection caused by a virus selected from the group consisting of HIV and a drug-resistant strain thereof, SARS-CoV2 and a mutant strain thereof, MERS-CoV, EBOV, MARV, IAV, RABV and VSV. In some embodiments, the viral infection is an infection caused by HIV or a drug-resistant strain thereof.

[0091] In some embodiments, mutant strains of SARS-CoV-2 include Alpha mutant strains, Beta mutant strains, Gamma mutant strains, Epsilon mutant strains, Delta mutant strains, Omicron mutant strains, etc. In some embodiments, mutant strains of SARS-CoV-2 include SARS-CoV-2 D614G and BA4 / 5 Omicron mutant strains. In some embodiments, IAV includes Influenza A, Influenza B, and Influenza C viruses. In some embodiments, the Influenza A virus includes Petition 870250105357, dated 11 / 18 / 2025, pp. 121 / 171 29 / 60 subtypes such as H1N1, H3N2, H5N1 and H7N9. In some manifestations, the Influenza A virus is H7N9.

[0092] In practice, the lipopeptide or polypeptide, as described in this disclosure, may be administered to a patient as a medicament, directly or in a mixture with a suitable vehicle or excipient, for the purpose of treating and / or preventing a viral infection (e.g., HIV, etc.) or a disease caused by viral infection. The vehicle material includes, but is not limited to, water-soluble vehicle material (e.g., polyethylene glycol, polyvinylpyrrolidone, organic acid, etc.), sparingly soluble vehicle material (e.g., ethyl cellulose, cholesterol stearate, etc.), enteric-soluble vehicle material (e.g., cellulose acetate phthalate, carboxymethyl cellulose, etc.), with water-soluble vehicle material being preferred.Using these materials, various dosage forms can be prepared, including, but not limited to, tablets, capsules, dragees, aerosols, pills, powders, solutions, suspensions, emulsions, granules, liposomes, transdermal agents, buccal tablets, suppositories, lyophilized powder for injection, etc. The dosage form can be a conventional preparation, a sustained-release preparation, a controlled-release preparation, and various microparticle delivery systems. To formulate a single-dose dosage form in a tablet, a wide variety of vehicles known in the art can be used. Examples of vehicles include, for instance, diluents and absorbents such as starch, dextrin, calcium sulfate, lactose, mannitol, sucrose, sodium chloride, glucose, urea, calcium carbonate, kaolin, microcrystalline cellulose, and aluminum silicate; wetting and binding agents such as water, glycerol, polyethylene glycol, ethanol, propanol, starch paste, dextrin, syrup, honey, glucose solution, gum arabic, gelatin paste, sodium carboxymethylcellulose, shellac, methylcellulose, potassium phosphate, and polyvinylpyrrolidone; and disintegrants such as dry starch, alginate, agar powder, brown algae starch, and sodium bicarbonate. Petition 870250105357, dated 11 / 18 / 2025, pp. 122 / 171 30 / 60 and citric acid, calcium carbonate, polyoxyethylene, sorbitol fatty acid ester, sodium dodecyl sulfate, methyl cellulose and ethyl cellulose; disintegration inhibitor, such as sucrose, glyceryl tristearate, cocoa butter and hydrogenated oil; absorption promoters, such as quaternary ammonium salts and sodium lauryl sulfate; lubricant, such as talc, silica, corn starch, stearate, boric acid, liquid paraffin and polyethylene glycol. The tablet can also be formulated as a coated tablet, such as a sugar-coated tablet, film-coated tablet, enteric-coated tablet or double or multi-layer tablet. To formulate a unit preparation form in a tablet, a wide variety of vehicles known in the art can be used.Examples of vehicles include, for instance, diluents and absorbents such as glucose, lactose, starch, cocoa butter, hydrogenated vegetable oil, polyvinylpyrrolidone, Gelucire, kaolin, and talc; binders such as gum arabic, gum tragacanth, gelatin, ethanol, honey, liquid sugar, rice paste, and flour paste; and disintegrants such as agar powder, dry starch, alginate, sodium dodecyl sulfate, methylcellulose, and ethylcellulose. To formulate a unit preparation form in a suppository, a wide variety of vehicles known in the art can be used. Examples of vehicles include, for instance, polyethylene glycol, lecithin, cocoa butter, higher alcohol, higher alcohol ester, gelatin, and semi-synthetic glyceride.To formulate a unit form of preparation for injection, such as a solution, emulsion, lyophilized powder, and suspension, all conventional diluents can be used, for example, water, ethanol, polyethylene glycol, 1,3-propanediol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, and polyoxyethylene sorbitan fatty acid ester. Furthermore, to prepare an isotonic injection, sodium chloride, glucose, or glycerin in an appropriate quantity can be added to the injection preparation, and, in addition, conventional cosolvent, buffer, and pH adjusting agent can also be added. Petition 870250105357, dated 11 / 18 / 2025, pp. 123 / 171 31 / 60 In addition, if necessary, coloring agents, preservatives, perfumes, flavorings, sweeteners, and other materials may optionally be added to the pharmaceutical preparation. The above preparation forms may be administered by injection, including subcutaneous injection, intravenous injection, intramuscular injection, intracavitary injection, and similar methods; intraluminal administration, such as transrectal and vaginal administration; respiratory administration, such as nasal administration; and mucosal administration. Among the above routes of administration, injection is preferred.

[0093] The dosage of the lipopeptide or polypeptide in this disclosure depends on several factors, for example, the nature and severity of a disease to be prevented or treated, the gender, age, weight and individual response of a patient or animal, a specific ingredient used, a route of administration and a frequency of administration, etc. The above dose may be administered in a single unit dosage form or in multiple dosage forms (e.g., two, three or four) units.

[0094] The lipopeptide or polypeptide of this disclosure may be used directly alone for the treatment or prevention of a viral infection (e.g., HIV, etc.) or a disease caused by viral infection, or it may be used in combination with one or more antiviral drugs to achieve the goal of enhancing overall therapeutic effects. Antiviral drugs include, but are not limited to, reverse transcriptase inhibitors, protease inhibitors, entry inhibitors, integration inhibitors, maturation inhibitors, and the like.The reverse transcriptase inhibitors above may be one or more inhibitors selected from the group consisting of AZT, 3TC, ddI, d4T, ddT, TDF, Abacavir, Nevirapine, Efavirenz, Delavirdine, Azvudine, Ainuvirine and the like; the protease inhibitors above may be one or more inhibitors selected from the group consisting of Saquinavir mesylate, Indinavir, Ritonavir, Amprenavir, Kaletra, Nelfinavir mesylate and the like; the. Petition 870250105357, dated 11 / 18 / 2025, pp. 124 / 171 32 / 60 invasion inhibitors above may be one or more inhibitors selected from the group consisting of Maraviroc, TAK-779, T20, T2635, Sifuvirtide, Albuvirtide and the like; integration inhibitors above may be one or more inhibitors selected from the group consisting of Raltegravir, Dolutegravir, Elvitegravir and the like.

[0095] A therapeutically effective dose level specific to any individual patient will depend on several factors, including the disorder being treated and its severity; the activity of the specific active ingredient used; the specific composition used; the patient's age, weight, general health, gender, and diet; the timing of administration, the route of administration, and the excretion rate of a specific active ingredient used; the duration of treatment; a medication used in conjunction with the specific active ingredient used in combination or simultaneously; and similar factors well known in the medical field. For example, it is common practice in the field to begin with a dosage of an active ingredient at a level below that required to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved.In general, the lipopeptide or polypeptide of the present disclosure can be administered to a mammal, particularly a human, at a dosage between 0.001 mg / kg body weight / day and 1000 mg / kg body weight / day, as well as between 0.01 mg / kg body weight / day and 100 mg / kg body weight / day, and also between 0.1 mg / kg body weight / day and 10 mg / kg body weight / day. Brief Description of the Drawings

[0096] Figure 1A is a diagram showing the sequence structures of T20, C34, T1249, T2635, SFT, ABT, C34-Chol, LP-11 and LP-98; it is a diagram showing the structure and function of the HIV-1 gp41 fusion protein.

[0097] Figure 1B is a diagram showing the structures of Petition 870250105357, dated 11 / 18 / 2025, pp. 125 / 171 33 / 60 sequence of T20, C34, T1249, T2635, SFT, ABT, C34-Chol, LP-11 and LP-98, where is a polypeptide diagram, in which the underlined sequences are PBD, three amino acids inserted in the NHR pocket are marked in red and mutant amino acids are marked in green; Chol represents cholesterol molecules and C16 represents palmitic acid molecules.

[0098] Figure 2 is a diagram showing the sequence structures of viral membrane fusion inhibitors (including LP-121, LP-122, LP-123, LP-124, LP-125, LP-126, LP-127 and LP-128) provided in the examples of this disclosure, wherein the underlined sequences are PBD, three amino acids inserted in the NHR pocket are marked in red and mutant amino acids are marked in green; Chol in brackets represents cholesterol molecules.

[0099] Figure 3 shows the anti-HIV activity of the viral membrane fusion inhibitors provided in the examples of this disclosure, wherein A shows comparisons of anti-HIV activity between C34-LP1 and C34-LP2; B shows comparisons of anti-HIV activity of LP-121, LP-122 and LP-123, the HIV-1 strains used NL4-3 and JRFL are pseudoviruses, and SG3.1 is a replicative virus; the target cell used is a TZM-bl cell.

[00100] Figure 4 shows the anti-HIV activity of the viral membrane fusion inhibitors provided in the examples of this disclosure, where A shows the comparisons of anti-HIV activity between LP-122 and LP-124; B shows the comparisons of anti-HIV activity between LP-123 and LP-125, C shows the comparisons of anti-HIV activity between LP-126, LP-127 and LP-128, the HIV-1 strains used NL4-3 and JRFL are pseudoviruses, and SG3.1 is a replicative virus; the target cell used is a TZM-bl cell.

[00101] Figure 5 shows comparisons of the anti-HIV activity of LP-127 and LP-128 provided in the examples of this disclosure with T20, where A shows their inhibitory activities against the replicative stains of Petition 870250105357, dated 11 / 18 / 2025, pp. 126 / 171 34 / 60 HIV-1 SG3.1, JR-CSF, and 89.6 infect TZB-bI cells; B shows its inhibitory activity against replicative stains of HIV-1 SG3.1, LAI.2, and 89.6 infecting MT-4 cells.

[00102] Figure 6 shows the results of the broad-spectrum antiviral activity assessment of LP-127 and LP-128 provided in the examples of this disclosure, where inhibitory activities against SARS-CoV-2, MERS-CoV, EBOV, MARV, IAV (H7N9), RABV and VSV are evaluated with pseudovirus systems.

[00103] Figure 7 shows the results of the stability analysis of LP-127 and LP-128 provided in the examples of this disclosure.

[00104] Figure 8 shows the secondary structure and thermal stability of the membrane fusion inhibitors provided in the examples of this disclosure, as detected using circular dichroism (CD), wherein A shows the alpha helix content (left figure) and thermal stability (left figure) of the lipopeptides alone; B shows the alpha helix content (left figure) and thermal stability (left figure) of the complex formed between the lipopeptide and the N44 target sequence polypeptide. Sequence information

[00105] Information about the sequences involved in this disclosure is provided in Table 1 below. Table 1: Descriptions of the sequences SEQ ID NO. Names / descrição Information of the sequence 1 T20 AC-YTSLIHSLIEESQNQQEKNEQELLELDKWASLWNWF-NH2 2 C34 AC-WMEWDREINNYTSLIHSLIEESQNQQEKNEQELL-NH2 3 T1249 Ac-W Q EW EQKI TA LLE QA QIQQEKNE YEL QKLDKWASLWEWF-NH2 4 T2635 Ac-TTW EA WDR AIAEYAAR I EA LI RAA Q EQQEKNE AA LR EL-NH2 5 SFT Ac-SW ETW E REI E NYT RQI YR IL EESQ E QQ DR NE RD LLE-NH2 6 ABT Ac-W E EWDREINNYT K LIH E LIEESQNQQEKNEQELL-NH2 7 C34-Chol Ac-WMEWDREINNYTSLIHSLIEESQNQQEKNEQELL-GSG-C(Chol)- Petition: 870250105357, on November 18, 2025, p. 127 / 171 35 / 60 SEQ ID NO. Names / Description Sequence Information NH2 8 LP-11 Ac- E MTW E EW EKK\EEYT KKIEEILK-PEG8-K(C16)-NH2 9 LP-98 Ac-Y EQKI EE L LKKAEEQQ K KNE E EL KK LEK(Chol)-NH2 10 C34-LP1 Ac-WMEWDREINNYTSLIHSLIEESQNQQEKNEQELLGSGSGK(Chol)NH2 11 C34-LP2 Ac-WMEWDREINNYTSLIHSLIEESQNQQEKNEQELLEAAAKK(Chol)NH2 12 LP-121 Ac- EMTW E EW EKKIEELEKKI EE L LKKAEEQQ K KNEAAAKK(Chol)NH2 13 LP-122 Ac-TW E EW EKK I EELEKK I EE L LKKAEEQQ K KNEQEAAAKK(Chol)-NH2 14 LP-123 Ac-TWEEWEKKI EELEKKI EELLKKAEEQQKKNEAAAKK(Chol)-NH2 15 LP-124 Ac-TYE E YEKKI EELEKK I EE L LKKAEE QQ K KNEQEAAAKK(Chol)-NH2 16 LP-125 Ac-TYE E YEKK I EELEKK I EE L LKKAEE QQ K KNEAAAKK(Chol)-NH2 17 LP-126 Ac- EYE E YEKKI EELEKK I EE L LKKAEEQQ K KNEAAAKK(Chol)-NH2 18 LP-127 Ac-EYEE YEKELEELEKKI EELLKKAEEQQKKNEAAAKK(Chol)-NH2 19 LP-128 Ac-E YEK EL EELEKKIEE L LKKAEE QQ K KNEAAAKK(Chol)-NH2 20 N44 Ac-TVQARQLLSGIVQQQNNLLRAIEAQQHLLQLTVWGIKQLQARILNH2 21 Polipeptídeo 1 Ac-WMEWDREINNYTSLIHSLIEESQNQQEKNEQELLEAAAKK-NH2 22 Polipeptídeo 2 Ac-EMTWEEWEKKI EELEKKI EELLKKAEEQQKKN EAAAKK-NH2 23 Polypeptide 3 Ac-TW E EW EKK I EELEKK I EE L LKKAEEQQ K KNEQEAAAKK-NH2 24 Polypeptide 4 Ac-TWEEWEKKI EAAAKK EELLKKAEEQQKNEAAAKK-NH2 25 Polypeptide 5 Ac-TYE E ONE I EELEKK I EE L LKKAEE QQ K KNEQEAAAAKK-NH2 26 Polypeptide 6 Ac-TYE E ONE I EELEKK I EE L LKKAA KNEAK 27-KHAKK-NH2 Polypeptide 7 Ac-EEEE YEKKI EELEKKI EELLKAEEQQKN EAAAKK-NH2 28 Polypeptide 8 Ac-EYEE YEKELEELEKKI EELLKAEEQQKNEAAAKK-NH2 29 Polypeptide 9 Ac-EEEE YEKKI EELEKKI EELLKKAEEQQKKN-NH2 EAAAKK-NH2 Note: the underlined sequences are PBD, the three amino acids inserted in the NHR pocket are labeled in bold and the mutated amino acids are labeled in italics; Chol represents the cholesterol molecule and C16 represents the palmitic acid molecules. Examples

[00106] The present disclosure will be described in detail below, with reference to specific embodiments, and the examples given herein serve only to illustrate the present disclosure, but not to limit its scope. The examples below serve as guidance for a professional with common knowledge in the field to make modifications, but not Petition 870250105357, dated 11 / 18 / 2025, pp. 128 / 171 Sections 36 / 60 impose no limitations on this disclosure in any way. A professional with knowledge in the field may consult this disclosure to appropriately modify the related parameters. Specifically, it is necessary to indicate that all similar substitutions or alterations are obvious to a professional with knowledge in the field, and all of them are considered within the scope of this disclosure. The method of this disclosure has been described with preferred examples, and it will be evident that the related person can obtain and apply the techniques of this disclosure by making appropriate modifications, alterations, or combinations to the compounds and preparation methods as described herein, without departing from the content, essence, and scope of this disclosure.

[00107] The experimental methods in the following examples, unless otherwise indicated, are conventional methods and are carried out in accordance with the techniques or conditions described in the literature of the field or in accordance with the product instructions. The materials, reagents and the like used in the following examples, unless otherwise indicated, are commercially available. Example 1: Preparation of lipopeptides that inhibit viral membrane fusion.

[00108] The cholesterol modifications of ten lipopeptides (C34-LP1, C34-LP2, LP-121, LP-122, LP-123, LP-124, LP-125, LP-126, LP-127 and LP-128) prepared in the examples of the present disclosure were each achieved by the amidation reaction between a cholesteryl bromoacetate and the amino group of the C-terminal (K) lysine side chain of the peptide chain, and the specific method was described in the literature published by the inventor's laboratory[7]. The amino terminals of all lipopeptides prepared in the examples of the present disclosure each had an acetyl (Ac) as an amino-terminal protecting group, and the carboxyl terminals each had an Petition 870250105357, dated 11 / 18 / 2025, pp. 129 / 171 37 / 60 amino (NH2) as a carboxy-terminal protecting group. I. Chemical reagents required in the preparation process

[00109] All chemical reagents, such as various amino acids Fmoc, N,N'-diisopropylcarbodiimide (DIC), 1-hydroxybenzotriazole (HOBt), N,N-dimethylformamide (DMF), piperidine (PIPE), ninhydrin, acetic anhydride (Ac2O), N,N-diisopropylethylamine (DIEA), hydrazine hydrate, cholesterol hemisuccinate, trifluoroacetic acid (TFA), ethanedithiol (EDT), thioanisole (TA), triisopropylsilane (TIPS), phenol and the like, were each purchased from major chemical reagent suppliers and were not purified before use. The amino acid-protective raw materials used in polypeptide synthesis included Fmoc-Lys(Dde)-OH, Fmoc-Lys(Boc)-OH, Fmoc-Trp(Boc)-OH, Fmoc-Met-OH, Fmoc-Thr(tBu)-OH, Fmoc-Glu(OtBu)-OH, FmocAsp(OtBu)-OH, Fmoc-Arg(Pbf)-OH, Fmoc-Ile-OH, Fmoc-Asn(Trt)-OH, FmocTyr(tBu)-OH, Fmoc-Ser(tBu)-OH, Fmoc-Leu-OH, Fmoc-Gln(Trt)-OH, Fmoc-GlyOH, and Fmoc-Ala-OH.The abbreviations among them have well-known meanings, for example: Fmoc is 9-fluorenylmethoxycarbonyl, Dde is 1-(4,4-dimethyl-2,6-dioxocyclohexylene)ethyl, Boc is t-butoxycarbonylacyl, tBu is t-butyl, OtBu is t-butoxy, Trt is trityl, and Pbf is (2,3-dihydro-2,2,4,6,7-pentamethylbenzofuran-5-yl)sulfonyl. II. Synthesis of Peptide Resins

[00110] Rink Amide MBHA resin was used as a carrier resin and was sequentially coupled with corresponding protected amino acids in polypeptide amino acid sequences via Fmoc deprotection and coupling reaction, to prepare peptide resins. I. Coupling of the first protected amino acid to the main chain.

[00111] 0.3 mmol of the first protected amino acid FmocLys(Dde)-OH and 0.3 mmol of HOBt were collected and dissolved with an appropriate amount of DMF; 0.3 mmol of DIC was additionally collected, Petition 870250105357, dated 11 / 18 / 2025, pp. 130 / 171 38 / 60 was slowly added to the protected amino acid DMF solution under stirring, and the resulting mixture was reacted at room temperature for 5 minutes under stirring to obtain an activated protected amino acid solution, which was reserved for later use.

[00112] 0.1 mmol of Rink Amide MBHA resin (0.35 mmol / g*0.3 g) were collected and deprotected with a 25% PIPE / DMF solution (volume ratio) for 20 minutes (twice), after washing and filtering, to obtain a resin with Fmoc removed.

[00113] The first activated protected amino acid solution was added to the resin with Fmoc removed to carry out a coupling reaction for 60 minutes, after filtration and washing, to obtain a resin containing the first protected amino acid Fmoc-Lys(Dde). .COUPLING OF OTHER PROTECTED AMINO ACIDS TO THE MAIN CHAIN

[00114] Using the same method above to couple the first protected amino acid to the main chain, the other corresponding protected amino acids of the polypeptide were coupled sequentially to obtain resins containing amino acids from the main chain. Finally, the N-terminal was encapsulated by acetylation with 0.3 mmol of Ac2O and 0.6 mmol of DIEA to complete the synthesis of the main chain. After the reaction in each of the above steps, the reaction was controlled by the Kaiser Test and, if the condensation reaction of a given amino acid was incomplete, the condensation was repeated once until the desired target peptide segment was obtained, i.e., the polypeptide as described in this disclosure. Cholesterol coupling to lysine side chains

[00115] The resin was treated with a 2% hydrazine hydrate / DMF (volumetric ratio) solution in as small a volume as possible to remove the Dde protecting group from the C-terminal lysine side chain (for 10 minutes, twice), after filtration and washing, to obtain a resin that had Petition 870250105357, dated 11 / 18 / 2025, pp. 131 / 171 39 / 60 Dde was removed and reserved for later use. 0.3 mmol of cholesteryl hemisuccinate and 0.3 mmol of HOBt were collected and dissolved with an appropriate amount of DMF; 0.3 mmol of DIC was additionally collected, slowly added to the DMF solution of cholesteryl hemisuccinate and HOBt, and the resulting mixture was reacted at room temperature for 5 minutes under stirring. The prepared solution containing cholesteryl hemisuccinate, HOBt, and DIC was added to the resin from which Dde had been removed to carry out a coupling reaction for 60 minutes, after filtration, washing, and drying, to obtain a peptide resin. III. Preparation of Raw Products

[00116] The above peptide resin was collected and added to a cleavage reagent (the cleavage agent is 15 mL / g of resin) and well mixed. The resulting mixture was reacted at 30 °C for 3 hours under stirring, thus cleaving the polypeptide of interest from the resin and removing the protecting group from the side chain. The filtrate of the reaction mixture was collected. The resin was washed with a small amount of TFA / DCM three times and, after combining the filtrates, the combined filtrates were precipitated by the addition of anhydrous ether and centrifuged. The filter cake was washed and precipitated with cold anhydrous ether a second time and then vacuum dried to obtain a white powder, i.e., the crude lipopeptide product. The cleavage reagent had the following composition: trifluoroacetic acid : 1,2-ethanedithiol : thioanisole : phenol : H2O : triisopropylsilane = 68.5 : 10 : 10 : 5 : 3.5 : 1 (v / v). IV. Preparation of Pure Products

[00117] The crude lipopeptide product above was collected and dissolved by the addition of water / acetonitrile, and the resulting mixture was centrifuged to remove insoluble substances and reserved for later use. A reversed-phase high-performance liquid chromatograph was used for purification. The chromatographic column used was an Agela C18 (10 μm, 100A, 50 χ 250 mm), with Petition 870250105357, dated 11 / 18 / 2025, pp. 132 / 171 A mobile phase consisting of mobile phase A (0.05% TFA and 2% acetonitrile in water) and mobile phase B (90% acetonitrile in water) was used. The mobile phase had a flow rate of 25 mL / min, and the ultraviolet detection wavelength was 220 nm. The crude product solution was loaded onto the chromatographic column to perform a gradient elution, and the corresponding purified components were collected and lyophilized directly to remove solvents, to obtain a pure polypeptide trifluoroacetate product in a fluffy state.

[00118] The pure trifluoroacetate product of the polypeptide was redissolved with water and acetonitrile, to which a large amount of anion exchange resin (in the form of an acetate radical) was added, the resulting mixture was stirred for 3 hours and filtered, and then the ion exchange resin was rinsed with a mixed solvent of water / acetonitrile, the filtrates were combined and lyophilized, to obtain a pure acetic acid salt product of the polypeptide in a fluffy state.

[00119] The chemical structure of the synthesized lipopeptide was characterized by MALDI-TOF mass spectrometry, and the purity was determined by high-performance analytical liquid chromatography (Agela C18-4.6 x 250 mm, flow rate: 1 mL / min). The results showed that the synthesized lipopeptides had a purity greater than 95%. Example 2: Effect of EAAAK rigid ligands on the anti-HIV activity of membrane fusion inhibitors.

[00120] The present example compared C34-LP1 (containing a flexible GSGSG ligand) and C34-LP2 (containing a rigid EAAAK ligand) in anti-HIV activity, and the materials and methods used were described in the literature published by the inventors' laboratory[7], where the viruses used were pseudoviruses of the NL4-3 and JRFL strains of HIV-1 and replicative viruses (live viruses) of the SG 3.1 strain of HIV-1. Petition 870250105357, dated 11 / 18 / 2025, pp. 133 / 171 41 / 60 I. Experimental Method

[00121] Virus preparation: Plasmids expressing NL4-3 or JRFL envelope protein (Env) were cotransfected with pSG3Δenv plasmids of the HIV-1 main structure into HEK293T cells; molecular clones encoding SG3.1 were transfected into HEK293T cells. The transfected cells were cultured in a cell culture incubator at 37 °C and 5% CO2 for 48 hours, and then the supernatant was collected and filtered to obtain the filtrate, which became a viral solution containing NL4-3 pseudovirus or JRFL pseudovirus or live SG3.1 virus, after titration, which was preserved at -80 °C for later use.

[00122] The test lipopeptides were dissolved in deionized water and then diluted with DMEM medium in a 3-fold serial dilution to obtain a lipopeptide diluent. 9 dilutions were defined for each test lipopeptide.

[00123] In a 96-well plate, lipopeptide diluent (50 μL / well) was added to the drug wells and DMEM medium (50 μL / well) was added to the control wells. Each well was filled with three duplicate wells. Then, a viral solution of 100 TCID50 (adjusted to 50 μL / well) was added and incubated at room temperature for 30 minutes.

[00124] TZM-b1 cells were resuspended in DMEM medium and DEAE-dextran was added to them so that the cell concentration was approximately 10*104 cells / mL and the DEAE-dextran concentration was 15 μg / mL. After completion of step (3), a TZM-b1 cell suspension (100 μg / well) was added to the 96-well plate and cultured for 48 hours in a cell culture incubator at 37 °C and 5% CO2.

[00125] The cell culture supernatant was discarded and 30 μL of a cell lysate (Promega, Cat. No.: E1531) was added to each well. Cell lysis was performed for 15 minutes at room temperature and, in Petition 870250105357, dated 11 / 18 / 2025, pp. 134 / 171 42 / 60 then, a substrate reagent for luciferase assay (Promega, Cat. No.: E1501) was added. Relative luminescence units (RLU) were measured using a microplate luminometer, an inhibition rate curve was plotted, and the half-maximum inhibition concentration (IC50) of the drug was calculated. RESULTS AND EXPERIMENTAL ANALYSIS

[00126] The results were shown in Figure 3A. The results showed that C34-LP1 inhibited NL4-3 pseudovirus and JRFL pseudovirus from infecting TZM-bl cells with mean IC50 values ​​of 55 pM and 69.4 pM, respectively, while C34-LP2 inhibited NL4-3 pseudovirus and JRFL pseudovirus from infecting TZM-bl cells with mean IC50 values ​​of 20.23 pM and 19.9 pM, respectively; C34-LP1 inhibited live SG3.1 virus from infecting MT-4 cells with a mean IC50 value of 15.44 pM, while C34-LP2 inhibited live SG3.1 virus from infecting MT-4 cells with a mean IC50 value of 3.2 pM. In comparison, the inhibitory activity of C34LP2 against the NL4-3 pseudovirus and the JRFL pseudovirus was approximately 3 and 4 times greater than that of C34-LP1, respectively; the inhibitory activity of C34LP2 against the live SG3.1 virus was approximately 5 times greater than that of C34-LP1.Experimental results showed that the rigid EAAAK ligands would help improve the anti-HIV activity of membrane fusion inhibitors. Example 3: Design and identification of the antiviral activity of membrane fusion inhibitors.

[00127] By directly comparing the anti-HIV activity of C34LP1 and C34-LP2, it was confirmed that the use of a rigid ligand EAAAK can improve the antiviral effect of lipopeptide membrane fusion inhibitors. The examples in this disclosure further prepared lipopeptides LP-121, LP-122, and LP-123, in which EAAAK was used as a ligand, and the amino acid pairs EE and KK were further introduced at the corresponding β, ε, γ positions of the CHR helix, respectively, to Petition 870250105357, dated 11 / 18 / 2025, pp. 135 / 171 43 / 60 promote the formation of a “salt bridge” structure. Using the method of Example 2, the anti-HIV activity of LP-121, LP-122, and LP-123 was determined. The results are shown in Figure 3B. The results showed that the IC50 values ​​of LP-121 against the NL4-3 pseudovirus, the JRFL pseudovirus, and the live SG3.1 virus were 51.98 pM, 42.39 pM, and 9.88 pM, respectively; the IC50 values ​​of LP-122 against the NL4-3 pseudovirus, the JRFL pseudovirus, and the live SG3.1 virus were 22.45 pM, 41.55 pM, and 9.05 pM, respectively; The IC50 values ​​of LP-123 against NL4-3 pseudovirus, JRFL pseudovirus, and live SG3.1 virus were 18.05 pM, 14.59 pM, and 3.68 pM, respectively. In comparison, it can be seen that the LP-123 lipopeptide containing a shorter sequence exhibited optimal anti-HIV activity, while the LP-121 lipopeptide with a prolonged N-terminal and the LP-122 lipopeptide with a prolonged C-terminal showed reduced anti-HIV activity.This unexpected result revealed the relationship between the structure and function of membrane fusion inhibitors. Example 4: Technical strategy for further optimization of membrane fusion inhibitors.

[00128] In order to further enhance the antiviral activity of membrane fusion inhibitors, the present disclosure creatively prepared the membrane fusion inhibitor lipopeptides LP-124 and LP-125. The two hydrophobic W amino acids of the N-terminal pocket-binding domain (PBD) in the polypeptide sequences of LP-122 and LP-123 were replaced by two hydrophilic, low molecular weight Y amino acids, to promote the conversion of the interaction between the inhibitors and the NHR target in the pocket domain from high hydrophobicity to hydrophilicity.

[00129] Similarly, using the experimental method of Example 2, the anti-HIV activities of LP-124 and LP-125 were determined and compared for analysis. Petition 870250105357, dated 11 / 18 / 2025, pp. 136 / 171 44 / 60

[00130] The results were shown in Figure 4A and Figure 4B. The results showed that the IC50 values ​​of LP-124 against pseudovirus NL4-3, pseudovirus JRFL, and live virus SG3.1 were 2.07 pM, 5.93 pM, and 1.06 pM, respectively, which were increased compared to the activity of its template LP-122 by approximately 11 times, 7 times, and 9 times, respectively. The IC50 values ​​of LP-125 against pseudovirus NL4-3, pseudovirus JRFL, and live virus SG3.1 were 3.43 pM, 5.78 pM, and 1.11 pM, respectively, which were increased compared to the activity of its template LP-123 by approximately 5 times, 3 times, and 3 times, respectively.

[00131] In addition, the examples in this disclosure prepared three lipopeptides LP-126, LP-127, and LP-128, and their anti-HIV activities were determined using the same method described above. The results are shown in Figure 4C. The results showed that the IC50 values ​​of LP-126, LP-127, and LP-128 against the NL4-3 pseudovirus were 3.85 pM, 5.01 pM, and 3.27 pM, respectively; the IC50 values ​​of LP-126, LP-127, and LP-128 against the JRFL pseudovirus were 6.08 pM, 5.63 pM, and 4.97 pM, respectively; The IC50 values ​​of LP-126, LP-127, and LP-128 against live SG3.1 virus were 1.65 pM, 2.31 pM, and 1.75 pM, respectively.

[00132] These results showed that in the PBD sequence of membrane fusion inhibitors, the substitution of amino acid W for amino acid Y could significantly increase antiviral activity. Example 5: Comparison and analysis of the anti-HIV activity of LP-127, LP-128 and T20

[00133] T20 is currently the only membrane fusion inhibitor that has been approved for clinical use by the U.S. Food and Drug Administration (FDA) for the treatment of HIV-1 infection. In the present example, multiple replicative HIV-1 strains were used to better evaluate the anti-HIV activities of LP-127 and LP-128, and their inhibitory activities were Petition 870250105357, dated 11 / 18 / 2025, pp. 137 / 171 45 / 60 compared to those of the T20. I. Experimental Method

[00134] The preparation method for the replicative HIV-1 strains SG3.1, JRCSF, 89.6 and LAI.2 was the same as described in Example 2, which were obtained by transfecting plasmids from molecular clones into HEK293T cells, and the specific method was described in the literature published by the inventor's laboratory[7]. The examples in this disclosure not only determined the activity of membrane fusion inhibitors that inhibit these viruses from infecting TZB-bI cells (the method was the same as in Example 2), but also determined the activity of membrane fusion inhibitors that inhibit these replicative HIV-1 strains from infecting MT-4 cells, with the specific experimental method below: (1) Lipopeptides were gradually diluted in a 96-well plate, setting up 3 replicate wells and 9 gradients, and then 200 TCID₂ viruses and approximately 4*10⁴ MT-4 cells were added to each well in order; (2) The plate was placed in an incubator at 37 °C and 5% CO2 for 4 hours, then centrifuged at 200 g at room temperature for 5 minutes, and then the supernatant was discarded. The cells were washed again with RPMI-1640 culture medium at 200 μl / well and then RPMI-1640 complete culture medium was added at 200 μl / well to culture the cells; (3) On the fourth day, the 96-well plate was centrifuged at room temperature at 200 g for 5 min, and the supernatant was collected at 30 μl / well and transferred to a new 96-well plate, to which 1% Triton-X100 solution was added at 120 μl / well to inactivate the viruses. The positive control wells and the initial concentration were used for P24 antigen quantification to determine the dilution factor. P24 antigen quantification was performed according to the operational method described in the kit specification, using a 96-well microplate reader for measurement. Then, Petition 870250105357, dated 11 / 18 / 2025, pp. 138 / 171 46 / 60 each culture supernatant was diluted to an appropriate concentration to conduct the quantitative P24 antigen assay. The inhibition curve for each drug was fitted using the four-parameter logistic equation in nonlinear regression analysis, and IC50 values ​​were calculated. RESULTS AND EXPERIMENTAL ANALYSIS

[00135] The results were shown in Figure 5.

[00136] In TZM-bl cells, LP-127, LP-128, and T20 inhibited SG3.1 with IC50 values ​​of 2.04 pM, 0.68 pM, and 2911.83 pM, respectively; inhibited JR-CSF with IC50 values ​​of 10.38 pM, 7.47 pM, and 5599 pM, respectively; and inhibited 89.6 with IC50 values ​​of 9.09 pM, 8.56 pM, and 15841.67 pM, respectively (in Figure 5A). In comparison, the inhibitory activities of LP-127 and LP-128 against SG3.1 were greater than those of T20 by 1427 times and 4282 times, respectively; The inhibitory activities against JR-CSF were 539 times and 750 times greater than those of T20, and the inhibitory activities against 89.6 were 1743 times and 1851 times greater than those of T20, respectively.

[00137] In MT-4 cells, LP-127, LP-128, and T20 inhibited SG3.1 with IC50 values ​​of 0.69 pM, 0.4 pM, and 1133.7 pM, respectively, inhibited LAI.2 with IC50 values ​​of 0.27 pM, 0.08 pM, and 745.77 pM, respectively, and inhibited 89.6 with IC50 values ​​of 1.45 pM, 0.83 pM, and 4801.5 pM, respectively (in Figure 5B). In comparison, the inhibitory activities of LP-127 and LP-128 against SG3.1 were 1643-fold and 2834-fold, respectively, greater than those of T20; The inhibitory activities against LAI.2 were greater than those of T20 by 2762 times and 9322 times, respectively; and the inhibitory activities against 89.6 were greater than those of T20 by 3311 times and 5785 times, respectively. Example 6: Broad-spectrum anti-HIV activity of membrane fusion inhibitors

[00138] HIV has high variability and evolves into various Petition 870250105357, dated 11 / 18 / 2025, pp. 139 / 171 47 / 60 subtypes and recombinant viruses, with HIV-1 subtypes A, B, and C being the main contributors to the AIDS pandemic, while in China, recombinant viruses A / E and B / C are the main ones. The present example further evaluated the broad-spectrum anti-HIV activities of the membrane fusion inhibitors of this disclosure through a set of cell fusion experiments using pseudoviruses from 12 globally representative pandemic strains of HIV-1 and compared and analyzed the activities with those of T20. I. Experimental Method

[00139] The materials and methods used were described in the literature published by the inventors' laboratory[7]. The method of preparing the HIV-1 pseudoviruses and the antiviral experiment were the same as the methods described in Example 2. The cell-cell fusion inhibition activity mediated by the HIV-1 envelope protein (Env) was detected using a cell fusion experiment based on a DSP fluorescence reporting system: (1) 293T cells (effector cells) were spread in a 96-well plate (at approximately 1.5*104 cells / well), and 293FT target cells (approximately 1.5χ104 cells / mL) stably expressing CXCR4 / CCR5 and DSP8-11 were spread in a 10 cm cell culture plate and then placed under 37 °C and 5% CO2 conditions for culture; (2) After 16 hours of culture, the HIV-1 Env expression plasmid and the DSP1-7 plasmid were cotransfected into 293T effector cells in a 1:1 ratio; (3) After 24 hours of transfection, a membrane fusion inhibitor was dissolved in deionized water and diluted to the initial concentration with DMEM medium, being added to the effector cells (50 μL / well) in the 96-well plate in a triple serial dilution, with 9 dilutions and 3 duplicate wells. The control group was treated with DMEM medium without the inhibitor. The plate was incubated at 37 °C with 5% CO2 for 1 hour; Petition 870250105357, dated 11 / 18 / 2025, pp. 140 / 171 48 / 60 (4) 293FT cells were resuspended to adjust the cell concentration to approximately 30x104 cells / mL, and live cell substrate EnduRen (Promega) was added at a ratio of 1:4000 and thoroughly mixed. The mixture was incubated under conditions of 37 °C and 5% CO2 for 30 minutes; (5) 293FT cells were added to HIV-1 effector cell wells at 100 μύ / well. The plate was centrifuged for 1 minute at 300 g to make full contact between effector cells and target cells. After the mixture was cultured at 37 °C for 1 hour, luciferase activity (relative luminescence units, RLU) was detected, the inhibition rate curve was plotted, and the concentration-half inhibition (IC50) of the drug was calculated. RESULTS AND EXPERIMENTAL ANALYSIS

[00140] The inhibitory results of the membrane fusion inhibitors of the present disclosure against pseudovirus infections of the representative pandemic strain of HIV-1 were shown in Table 2. The T20 polypeptide inhibited 12 pseudoviruses with a mean IC50 value of 20052.09 pM, while the four lipopeptides LP-123, LP-125, LP-127 and LP-128 inhibited 12 pseudoviruses with mean IC50 values ​​of 27.39 pM, 4.22 pM, 4.89 pM and 3.19 pM, respectively. In comparison, the inhibitory activities of LP-123, LP-125, LP-127, and LP-128 against 12 pseudoviruses were greater than those of T20 by 732 times, 4752 times, 4101 times, and 6286 times, respectively. Table 2. Shows the inhibitory activities of T20 and LP-123, LP-125, LP-127, and LP-128 provided in the examples of the present invention against representative pseudoviruses of the pandemic strain of HIV-1. Inhibitory activity during pseudovirus infection (IC50 ± SD, HIV-1 Subtype M strain) T20 LP-123 LP-125 LP-127 LP-128 20520.00 ± 12.79 ± 398-F1 F6 20 A , 3.91 ± 0.47 3.21 ± 0.08 2.39 ± 0.52 1602.77 3.82 6799.50 ± 30.02 ± TRO.11 B 5.19 ± 0.66 5.05 ± 1.2 2.69 ± 0.27 351.90 1.57 Petition 870250105357, dated 11 / 18 / 2025, pp. 141 / 171 49 / 60 HIV-1 Strain Subtype Inhibitory Activity During Pseudovirus Infection (IC50 ± SD, pM) T20 LP-123 LP-125 LP-127 LP-128 X2278_C2_B6 B 5536.33 ± 175.36 12.27 ± 1.19 1.76 ± 0.21 2.61 ± 0.72 2.18 ± 0.69 CE703010217_B6 C 43361.17 ± 2155.49 29.74 ± 0.84 4.19 ± 0.42 4.36 ± 0.17 2.47 ± 0.25 HIV_25710-2.43 C 13473.67 ± 359.21 25.04 ± 4.07 3.59 ±0.28 2.96 ±0.83 1.92 ±0.57 CE1176_A3 C 8425.34 ± 37.71 34.41 ± 9.87 7.73 ±0.34 7.34 ±0.29 4.95 ±1.10 x1632-s2-b10 ± 44.55 13.69± 0.70 5.25 ± 0.28 3.05 ±0.69 2.49 ±0.01 CNE8 A / E 23862.34 ± 1308.62 49.69 ± 12.08 6.15 ±0.09 8.16 ±3.46 3.74 ±1.12 CNE55 A / E 26101.17 ± 1364.48 59.73 ± 3.96 3.70 ±0.01 6.44 ± 0.35 6.00 ± 0.04 CH119.10 B / C 13108.33 ± 2254.26 13.86 ± 0.55 1.48 ±0.01 2.25 ± 0.42 1.45 ±0.24 BJOX002000.03.2 B / C 26722.17 ± 568.75 28.52 ± 0.64 2.85 ± 0.05 7.46 ± 1.6 4.66 ± 0.66 Mean IC50 20052.09 27.39 4.22 4.89 3.19

[00141] The inhibitory results of the fusion inhibitors of. The inhibitory activity of the present disclosure against cell fusion mediated by the representative pandemic strain of HIV-1 Env is shown in Table 3. The T20 polypeptide inhibited membrane fusions of 12 viruses with a mean IC50 value of 11214.53 pM, while the four lipopeptides LP-123, LP-125, LP-127, and LP-128 inhibited membrane fusion of 12 viruses with mean IC50 values ​​of 24.04 pM, 11.9 pM, 4.97 pM, and 4.02 pM, respectively. In comparison, the inhibitory activities of LP-123, LP-125, LP-127, and LP-128 against membrane fusions of 12 viruses were greater than those of T20 by 466 times, 942 times, 2256 times, and 2790 times, respectively. Petition 870250105357, dated 11 / 18 / 2025, pp. 142 / 171 50 / 60 Table 3 shows the inhibitory activities of T20 and LP-123, LP-125, LP-127, and LP-128 provided in the examples of the present invention against cell fusion mediated by pandemic strains representative of HIV-1. Inhibitory activity against membrane fusion (IC50 ± SD, pM) HIV strain -1 Subtype----------------------------------------------------------T20 LP-123 LP-125 LP-127 LP-128 398-F1_F6_20 A 7166.33 ± 1728.26 17.52 ± 1.63 6.34 ± 0.83 3.56 ± 0.4 3.60 ± 0.34 TRO.11 B 29786.67 ± 2439.72 58.11 ± 4.76 53.53 ± 11.08 6.75 ±0.59 8.07 ± 0.98 5887.33 ± 472.06 9.47 ± 0.56 9.97 ± 2.29 8.24 ± 0.64 5.89 ± 1.17 HIV_25710-2.43 C 15793.33 ± 4658.57 27.25 ± 4.67 4.77 ± 0.78 4.54 ± 0.56 3.24 ± 0.42 CE1176_A3 C 6848.67 ± 1415.15 46.89 ± 4.94 26.63 ±3.64 6.22 ±0.13 3.37 ±0.21 X1632-S2-B10 G 3250.00 ± 943.87 26.79 ± 2.55 3.84 ± 0.58 3.30 ± 0.44 3.86 ± 0.29 246_F3_C10_2 A / C 3458.67 ± 162.89 8.70 ± 2.28 1.53 ± 0.08 1.43 ± 0.23 1.30 ± 0.67 CNE8 A / E 42543.33 ± 3248.94 48.27 ± 1.37 10.93 ± 1.29 12.76 ± 3.89 9.01 ± 0.16 CNE55 A / E 11090.00 ± 1752.83 14.71 ± 2.91 11.60 ± 1.52 7.42 ± 3.24 5.26 ± 0.45 CH119.10 B / C 1524.73 ± 513.44 10.66 ± 1.07 2.42 ± 0.25 1.11 ± 0.24 1.15 ± 0.10 BJOX002000.03.2 B / C 3472.00 ± 904.04 9.33 ±0.3 5.60 ±0.91 1.77 ±0.49 0.89 ± 0.22 Media IC50 11214.53 24.04 11.9 4.87 4.02 Example 7: Inhibitory activity of membrane fusion inhibitors of PRESENT DISCLOSURE AGAINST T20-RESISTANT VIRUS STRAINS

[00142] Another important biological characteristic of HIV is its propensity for drug resistance, resulting in treatment failures. Petition 870250105357, dated 11 / 18 / 2025, pp. 143 / 171 51 / 60, this being a fundamental problem to be solved in drug research and development. The present example evaluated the antiviral activities of the membrane fusion inhibitors disclosed herein using a group of highly T20-resistant mutant strains, and compared and analyzed their inhibitory activities with that of the lipopeptide LP98. I. Experimental Method

[00143] Based on the NL4-3 strain of HIV-1, a group of twelve T20-resistant mutant strains (L33S, I37T, V38A, V38M, Q40H, N43K, L33S / I37T, G36S / V38M, I37T / N43K, V38A / N42T, L33S / V38A / N42T, N43K / E49A / N126K) with a single mutation, a double mutation, or a triple mutation was constructed, and the construction method was described in the literature published by the inventors' laboratory[7]

[11]

[12] . The method of preparing the mutant strain pseudoviruses and the antiviral experiment were the same as the methods described in Example 2. RESULTS AND EXPERIMENTAL ANALYSIS

[00144] The results were shown in Table 4. The results showed that LP-98 inhibited 12 drug-resistant mutant strains with a mean IC50 value of 2,663.27 pM, while LP-123, LP-125, LP-127, and LP-128 inhibited 12 drug-resistant mutant strains with mean IC50 values ​​of 55.51 pM, 6.29 pM, 7.02 pM, and 9.13 pM, respectively. In comparison, the inhibitory activities of LP-123, LP-125, LP-127, and LP-128 against 12 drug-resistant mutant strains were greater than those of LP-98 by 48 times, 423 times, 379 times, and 292 times, respectively. Therefore, the membrane fusion inhibitors of the present disclosure had potent inhibitory activities against T20-resistant virus strains, reflecting a notable advantage in drug delivery capability. Petition 870250105357, dated 11 / 18 / 2025, pp. 144 / 171 52 / 60 Table 4 shows the inhibitory activities of LP-98 and LP-123, LP-125, LP-127 and LP-128 provided in the examples of the present invention against drug-resistant HIV-1 strains. NL4-3 Mutant Strain Inhibitory Activity (IC50 ± SD, pM) LP-98 LP-123 LP-125 LP-127 LP-128 L33S 203.53 ± 46.08 53.02 ± 4.48 7.24 ± 0.06 5.75 ± 0.68 3.83 ± 0.25 I37T 12.44 ± 0.71 43.55 ± 6.2 5.75 ± 0.06 5.75 ± 0.23 3.86 ± 0.12 V38A 104.12 ± 38.90 44.02 ± 10.46 5.15 ± 0.46 4.37 ±0.16 3.92 ±1.09 V38M 61.40 ± 10.41 42.53 ±8.03 5.71 ±0.30 4.80 ±0.18 3.29 ±0.11 Q40H 30.89 ± 3.43 39.62 ±2.81 5.59 ± 0.33 3.77 ±0.69 4.17 ±0.29 N43K 137.84 ± 18.17 28.9 ±4.65 5.60 ± 0.55 3.58 ±0.54 3.34 ± 0.42 L33S / I37T 2435.44 ± 278.44 73.96 ± 14.84 6.70 ± 0.30 7.20 ± 1.35 10.50 ±2.74 G36S / V38t7 18.85 ±4.51 62.85 ±8.70 8.78 ±1.68 6.21 ±0.12 5.11 ±0.67 Ι37Τ / Ν43Κ 1496.40 ±465.84 102.99 ±9.45 6.82 ±0.31 14.21 ±2.30 23.15 ±3.50 V38A / N42T 451.19 ± 142.95 37.32 ± 0.96 3.57 ± 0.22 3.64 ± 0.65 4.80 ± 0.47 L33S / V38A / N42T 23526.22 ± 5876.48 50.84 ± 1.34 4.88 ± 0.64 12.52 ± 1.40 25.28 ± 6.14 N43K / E49A / N126K 3480.89 ± 351.44 86.53 ± 12.15 9.65 ± 0.99 12.39 ± 1.24 18.26 ± 1.92 Mean CI50 2663.27 55.51 6.29 7.02 9.13 Example 8: Broad-spectrum inhibitory activity of fusion inhibitors MEMBRANE OF THIS DISCLOSURE AGAINST OTHER VIRUSES

[00145] The present example evaluated the inhibitory activities of LP127 and LP-128 against SARS-CoV-2 and several other viruses using a pseudovirus system. Experimental Method

[00146] The pseudovirus preparation method is a well-established technology in the field and can be routinely used by a person skilled in the art. Methods for the preparation of SARS-CoV-2 D614G and BA4 / 5 mutant strains, MERS-CoV, IAV (H7N9) and VSV pseudoviruses and antiviral experiments have been described in the literature published by the inventors' laboratory[13l[14l

[15] . The preparation of EBOV, MARV and RABV pseudoviruses has also been described in Petition 870250105357, dated 11 / 18 / 2025, pp. 145 / 171 53 / 60 of the literature above, which were obtained by cotransfection of a plasmid encoding viral envelope proteins with the HIV-1 pNL4-3.luc.R plasmid structure into HEK293T cells, and the steps of the antiviral experiment were substantially consistent with the method described in Example 2, with the main differences being the type of target cells and the amount of pseudoviruses used. The target cell for the SARS-CoV-2 pseudovirus was 293T / ACE2; the target cells for the MERS-CoV, EBOV, and MARV pseudoviruses were Huh-7; the target cell for the H7N9 pseudovirus was MDCK; the target cell for the RABV and VSV pseudoviruses was HEK293T. The amount of each pseudovirus used was 1000 TCID50. RESULTS AND EXPERIMENTAL ANALYSIS

[00147] The results were shown in Figure 6. The inventors surprisingly discovered that lipopeptides LP-127 and LP-128 could effectively inhibit infection by two mutant strains of SARS-CoV-2, with LP-127 and LP-128 inhibiting the mutant strain D614G with IC50 values ​​of 27.4 nM and 25.12 nM, respectively; and inhibiting the mutant strain Omicron BA4 / 5 with IC50 values ​​of 26.56 nM and 23.51 nM, respectively. LP-127 and LP-128 inhibited MERS-CoV with IC50 values ​​of 382.72 nM and 455.67 nM, respectively; and inhibited EBOV with IC50 values ​​of 61.68 nM and 274.47 nM, respectively; It inhibited MARV with IC50 values ​​of 143.98 nM and 534.44 nM, respectively; it inhibited H7N9 with IC50 values ​​of 414.87 nM and 352.6 nM, respectively; it inhibited RABV with IC50 values ​​of 1731 nM and 1130 nM, respectively; and it inhibited VSV with IC50 values ​​of 1509 nM and 1490 nM, respectively.

[00148] The experimental results above showed that LP127 and LP-128 could not only potently inhibit several HIV-1 subtypes and T20-resistant virus strains, but could also effectively inhibit several other viruses, and were broad-spectrum antiviral drug candidates. Petition 870250105357, dated 11 / 18 / 2025, pages 146 / 171 54 / 60 Example 9: In vitro cytotoxicity analysis of lipopeptides LP-127 and LP-128

[00149] To clarify the specificity of the antiviral activity and the pharmacology of the membrane fusion inhibitors LP-127 and LP-128 of this disclosure, the present example was further evaluated for its cytotoxicity in vitro. I. Experimental Method

[00150] In vitro cytotoxicity was detected using a CCK-8 cell proliferation / toxicity assay kit (manufacturer: Abbkine, Cat. No.: KTC 011001). The specific steps were as follows: (1) In a 96-well plate, the test lipopeptide was diluted in a 3-fold gradient, with 9 dilutions and three duplicate wells for each dilution; and each well contained 100 μL of a lipopeptide solution; control wells of DMEM medium (100 μL for each well) were set; (2) Approximately 10*104 cells / mL of test cell suspension (TZM-bl, MT-4, MDCK, Huh-7, Hep-2, HEK293T, 293T / ACE2) were added to the 96-well plate in step (1) at 100 μL / well, and cultured under conditions of 37 °C and 5% CO2 for 48 hours; (3) 20 μL of CCK-8 solution were added to each well and the plate continued to be incubated in an incubator for 2 hours; then the absorbance at 450 nm (OD 450) was measured with a microplate reader.Using GraphPad Prism software, the inhibition rate curve was fitted and the maximum cytotoxic concentration (CC50) of the drug was calculated. Experimental Results and Analyses

[00151] The results were shown in Table 5. The results showed that LP-127 had a mean CC50 of 15.68 μM in seven test cells, where the CC50 in TZM-bl cells was 10.21 μM, the CC50 in MT-4 cells was 15.45 μM, the CC50 in MDCK cells was 12.89 μM, the CC50 in Huh-7 cells was 31.28 μM, the CC50 in Hep-2 cells was 16.46 μM, the CC50 in HEK293T cells was 9.07 μM, the CC50 in 293T / ACE2 cells was 14.42 μM. The results showed that LP-128 had a mean CC50 of 19.91 μM in seven test cells. Petition 870250105357, dated 11 / 18 / 2025, pages 147 / 171 55 / 60 where the CC50 in TZM-bl cells was 7.49 μM, the CC50 in MT-4 cells was 28.22 μM, the CC50 in MDCK cells was 18.05 μM, the CC50 in Huh-7 cells was 40.28 μM, the CC50 in Hep-2 cells was 12.48 μM, the CC50 in HEK293T cells was 8.72 μM, and the CC50 in 293T / ACE2 cells was 24.1 μM. Table 5. Shows the in vitro cytotoxicity assessment of LP-127 and LP-128 provided in the examples of the present invention. Cell CC50 ± DP (μΜ) LP-127 LP-128 TZM-bI 10.21 ± 0.39 7.49 ± 1.46 MT-4 15.45 ± 2.22 28.22 ± 0.01 MDCK 12.89 ± 4.40 18.05 ± 6.39 Huh-7 31.28 ± 6.31 40.28 ± 12.40 Hep-2 16.46 ± 3.89 12.48 ± 2.28 HEK293T 9.07 ± 2.35 8.72 ± 2.16 293T / ACE2 14.42 ± 2.20 24.10 ± 2.48 Average CC50 15.68 19.91

[00152] With CC50 / IC50 analyses, it was observed that both LP127 and LP-128 presented a very high selective therapeutic index (SI). Example 10: Stability research of lipopeptides LP-127 and LP-128

[00153] In order to further investigate the drug delivery capability of the membrane fusion inhibitors of the present disclosure, in the present example, LP-127 and LP-128 were placed at room temperature or 37 °C for a long time, incubated with human serum, or digested with protease, and then their stability was evaluated by detecting changes in antiviral activity. I. Experimental Method

[00154] Temperature stability experiment: Aqueous solutions of LP-127 or LP-128 at a concentration of 300 μM were placed at room temperature or 37 °C for various periods of time and then their activities inhibiting NL4-3 pseudoviruses from infecting TZM-bl cells were determined by the same method as Example 2. Petition 870250105357, dated 11 / 18 / 2025, pp. 148 / 171 56 / 60

[00155] Human serum stability experiment: 20% human serum was mixed with LP-127 or LP-128 to a final concentration of 150 μm; the resulting mixture was incubated at 37 °C for 0, 5, 30, 60, 120, 180 or 240 minutes, and then its activities inhibiting NL4-3 pseudoviruses from infecting TZM-bl cells were determined by the same method as in Example 2.

[00156] Protease Digestion: LP-127 or LP-128 was mixed with protease K, trypsin, or α-chymotrypsin (Sigma-Aldrich products, Cat. No.: P2308, T4799, and C4129, respectively) in a 20:1 ratio (final concentrations were 2 mg / mL and 0.1 mg / mL, respectively); the resulting mixtures were incubated at 37 °C for 0, 30, 60, 120, 180, or 240 minutes, respectively, and then their activities inhibiting NL4-3 pseudoviruses from infecting TZM-bl cells were determined by the same method as in Example 2. RESULTS AND EXPERIMENTAL ANALYSIS

[00157] The results were shown in Figure 7. Compared with untreated lipopeptides (when the incubation time is 0), after treatment at different temperatures, with human serum or with three proteases for various periods of time, there was no significant change in the antiviral activity of LP-127 and LP-128, indicating that they were highly stable. Example 11: Structural characteristics of the membrane fusion inhibitor helix of the present disclosure and bond stability analyses. OF THE SAME

[00158] To analyze the structural characteristics of the membrane fusion inhibitors of the present disclosure and investigate their mechanism of action, a circular dichroism (CD) technique was used to determine the secondary structure (α-helix) and thermal stability of LP-121, LP-122, LP-123, LP-124, LP-125, LP-126, LP-127 and LP-128, as well as their complexes with the target sequence N44. I. Experimental Method

[00159] The method for determining CD and the synthesis and preparation Petition 870250105357, dated 11 / 18 / 2025, pp. 149 / 171 57 / 60 of the N44 polypeptide (AcTVQARQLLSGIVQQQNNLLRAIEAQQHLLQLTVWGIKQLQARIL-NH2), which were derived from the NHR sequence of gp41 and served as a simulated inhibitor target, were described in the literature published by the inventors

[16] .

[00160] Test lipopeptides and a mixture of N44 and lipopeptides were dissolved in phosphate-buffered saline (PBS) at pH 7.2, respectively, to obtain solutions with final concentrations of lipopeptides and N44 polypeptide of 10 μM. Each solution was placed in a water bath at 37 °C for 30 minutes and then transferred to a corresponding cuvette. A JASCO spectropolarimeter (Model J-815) was used to scan the changes in molar ellipticity [θ]λ of the solution in the wavelength range of 195–270 nm. The typical α-helical structure can exhibit maximum negative peaks at 208 nm and 222 nm. The PBS blank control was subtracted to correct the spectrum values. During the calculations, the peak value of -33000 degrees.cm2.dmol-1 was used as a standard for 100% α-helix content; the percentages of α-helix content of the polypeptides were calculated according to the molar ellipticity of the solution at 222 nm.Subsequently, the solution was added to a corresponding cuvette to detect thermal stability, and the CD temperature control module was set to scan the polypeptide solution at a rate of 2 °C / min to detect temperature-dependent changes in [θ]222 in the range of 20-98 °C. The melting curve was plotted and smoothed, and the midpoint temperature (Tm) value of the thermal dissociation transition was calculated using Origin software to reflect the degree of thermal stability of the helix. RESULTS AND EXPERIMENTAL ANALYSIS

[00161] The results were shown in Figure 8.

[00162] As shown in Figure 8A, the α-helix content of LP121, LP-122, LP-123, LP-124, LP-125, LP-126, LP-127 or LP-128 alone was Petition 870250105357, dated 11 / 18 / 2025, pages 150 / 171 58 / 60 69%, 65%, 56%, 64%, 78%, 51%, 57%, or 66%, respectively, indicating that each lipopeptide inhibitor on its own had a high helicity, with LP-125 having the highest helicity. However, its Tm value could not be accurately calculated according to the melting curve.

[00163] As shown in Figure 8B, the α-helix content of the mixture of LP-121, LP-122, LP-123, LP-124, LP-125, LP-126, LP-127 or LP-128 and N44 was 81%, 81%, 79%, 79%, 89%, 66%, 68% or 84%, respectively, and the Tm values ​​were >98 °C, >98 °C, >98 °C, 86 °C, 91 °C, 92 °C, 92 °C or 90 °C, respectively, indicating that lipopeptide inhibitors could interact with N44 to form a more stable α-helix structure, especially the three lipopeptides (LP-121, LP-122, LP-123) with a PBD containing the amino acid W. The results also indicated that replacing W with Y could reduce the binding capacity of PBD, but lipopeptides containing Y still had relatively high binding stability (Tm >86 °C).

[00164] This disclosure has been described in detail above. Provided it does not depart from the spirit and scope of this disclosure and there is no need to conduct unnecessary experiments, a professional with knowledge in the field could implement this disclosure on a broad scale, with equivalent parameters, concentrations, and conditions. Although this disclosure provides special examples, it is important to note that it can be modified. In general, according to the principles of this disclosure, this disclosure is intended to cover any changes, uses, or improvements to this disclosure, including changes made with routine techniques known in the field that deviate from the scope disclosed in this disclosure. According to the scope of the claims appended below, some basic features can be applied. The references 1. Chan DC, Kim PS. HIV entry and its inhibition. Cell 1998, 93: 681 - Petição 870250105357, de 18 / 11 / 2025, pág. 151 / 171 59 / 60 684; 2. He Y Synthesized peptide inhibitors of HIV-1 gp41-dependent membrane fusion. Curr Pharm Des 2013, 19: 1800-1809; 3. Dwyer JJ, Wilson KL, Davison DK, Freel SA, Seedorff JE, Wring SA, et al. Design of helical, oligomeric HIV-1 fusion inhibitor peptides with potent activity against enfuvirtide-resistant virus. Proc Natl Acad Sci U S A 2007, 104: 12772-12777; 4. He Y, Xiao Y, Song H, Liang Q, Ju D, Chen X, et al. Design and evaluation of sifuvirtide, a novel HIV-1 fusion inhibitor. J Biol Chem 2008, 283: 11126-11134; 5. Chong H, Yao X, Zhang C, Cai L, Cui S, Wang Y, et al. Biophysical property and broad anti-HIV activity of albuvirtide, a 3maleimimidopropionic acid-modified peptide fusion inhibitor. PLoS One 2012, 7: e32599; 6. Ingallinella P, Bianchi E, Ladwa NA, Wang YJ, Hrin R, Veneziano M, et al. Addition of a cholesterol group to an HIV-1 peptide fusion inhibitor dramatically increases its antiviral potency. Proc Natl Acad Sci U S A 2009, 106: 5801-5806; 7. Xue J, Chong H, Zhu Y, Zhang J, Tong L, Lu J, et al. Efficient treatment and pre-exposure prophylaxis in rhesus macaques by an HIV fusioninhibitory lipopeptide. Cell 2022, 185: 131-144 e118; 8. Yu D, Zhu Y, Jiao T, Wu T, Xiao X, Qin B, et al. Structure-based design and characterization of novel fusion-inhibitory lipopeptides against SARSCoV-2 and emerging variants. Emerg Microbes Infect 2021, 10: 1227-1240; 9. Zhou J, Xu W, Liu Z, Wang C, Xia S, Lan Q, et al. A highly potent and stable pan-coronavirus fusion inhibitor as a candidate prophylactic and therapeutic for COVID-19 and other coronavirus diseases. Acta Pharm Sin B 2021; Petição 870250105357, de 18 / 11 / 2025, pág. 152 / 171 60 / 60 10. Outlaw VK, Bovier FT, Mears MC, Cajimat MN, Zhu Y, Lin MJ, et al. Inhibition of Coronavirus Entry In Vitro and Ex Vivo by a Lipid-Conjugated Peptide Derived from the SARS-CoV-2 Spike Glycoprotein HRC Domain. mBio 2020,11:e01935-01920; 11. 11. Hu Y, Yu W Geng X, Zhu Y, Chong H, He Y In Vitro Selection and Characterization of HIV-1 Variants with Increased Resistance to LP-40, Enfuvirtide-Based Lipopeptide Inhibitor. Int J Mol Sci 2022, 23; 12. Wu X, Liu Z, Ding X, Yu D, Wei H, Qin B, et al. Mechanism of HIV-1 Resistance to an Electronically Constrained alpha-Helical Peptide Membrane Fusion Inhibitor. J Virol 2018, 92: e02044-02017; 13. Yu D, Zhu Y, Yan H, Wu T, Chong H, He Y. Pan-coronavirus fusion inhibitors possess potent inhibitory activity against HIV-1, HIV-2, and simian immunodeficiency virus. Emerg Microbes Infect 2021, 10: 810-821; 14. Zhu Y, Hu Y, Liu N, Chong H, He Y Potent inhibition of diverse Omicron sublineages by SARS-CoV-2 fusion-inhibitory lipopeptides. Antiviral Res 2022, 208: 105445; 15. Zhu Y Yu D, Hu Y, Wu T, Chong H, He Y SARS-CoV-2derived fusion inhibitor lipopeptides exhibit highly potent and broad-spectrum activity against divergent human coronaviruses. Signal Transduct Target Ther 2021, 6: 294; 16. Zhu Y, Ding X, Yu D, Chong H, He Y. The Tryptophan-Rich Motif of HIV-1 gp41 Can Interact with the N-Terminal Deep Pocket Site: New Insights into the Structure and Function of gp41 and Its Inhibitors. J Virol 2019, 94: effff1234. Petição 870250105357, de 18 / 11 / 2025, pág. 153 / 171

Claims

1 / 10 Claims 1. A LIPOPEPTIDE or a salt, a solvate, a hydrate, a complex, a chelate, a non-covalent complex or a pharmaceutically acceptable prodrug thereof, characterized by comprising a polypeptide or a variant thereof and a modification group linked to the C-terminal of the polypeptide or variant thereof by means of a linker, and optionally a terminal protecting group of the polypeptide, (X1X2X3)mX4X5X6X7X8X9X10X11X12X13X14X15IX16X17LX18X19X20X21 X22X23QQX24X2 5N(EX26)n Formula I wherein, the polypeptide is represented by Formula I, the modification group is a lipophilic compound, the linker is -(EAAAK)m-, -(XP)n2-, (EAAAK)n1-X27- or -(XP)n2-X27-; X1 is T, E, or S; X2 is W or a hydrophilic amino acid; X3 is E, M, or Q; m is O or I; X4 is E, A, or T; X5 is W or a hydrophilic amino acid; X6 is E or R; X7 is R, K, or Q; X8 is E, K, or A; X9 is L or I; X10 is E, N, or A; X11 is E or N; X12 is L or Y; X13 is E, T, or A; X14 is K, S, R, or A; Petition 870250105357, dated 11 / 18 / 2025, p.154 / 171 2 / 10 Xi5 is K, L, R, or Q; Xi6 is E, H, T, or Y; X17 is E, S, R, or A; Xi8 is L or I; X19 is K, E, or R; X20 is K, E, Q, or A; X21 is A or S; X22 is E or Q; X23 is E, N, or I; X24 is K, E, or D; X25 is K or R; X26 is Q, E, R, A, or Y; n is 0 or 1; X is any amino acid; X27 is K or C; n1 is a natural number between 1 and 5; n2 is a natural number between 1 and 5; and the variant differs from the polypeptide from which the variant is derived only in the substitution of one or more amino acid residues, and retains the biological function of the polypeptide from which the variant is derived.

2. LIPOPEPTIDE, according to claim 1, characterized by having one or more of the following features: - X1 is T or E; - X2 is W, D, E, H, K, Q, R, S, T or Y; - X3 is E or M; - X4 is E; - X5 is W, D, E, H, K, Q, R, S, T or Y; - X6 is E; Petition 870250105357, dated 11 / 18 / 2025, page 155 / 171 3 / 10 - X7 is R or K; - X8 is E or K; - Xio is E or N; - Xii is E; - Xi2 is L; - Xi3 is E or T; - Xi4 is K or S; - Xi5 is K or L; - Xi6 is E or H; - Xi7 is E or S; - Xi8 is L; - Xi9 is K or E; - X2 is K or E; - X21 is A; - X22 is E; - X23 is E or N; - X24 is K or E; - X25 is K; - X26 is Q; - X is A, K, or E.

3. LIPOPEPTIDE, according to claim 1, characterized by having one or more of the following features: - X2 is W or Y, preferably Y; - X3 is E; - X5 is W or Y, preferably Y; - X7 is K; - Xi0 is E; - Xi3 is E; Petition 870250105357, dated 11 / 18 / 2025, page 156 / 171 4 / 10 - Xi4 is K; - Xi5 is K; - Xi6 is E; - X17 is E; - Xi9 is K; - X2 is K; - X23 is E; - X24 is K.

4. LIPOPEPTIDE, according to any one of claims 1 to 3, characterized in that the polypeptide is represented by Formula I, Formula III, Formula IV or Formula V, Formula II (X1X2X3)mX4X5X6X7X8X9X10X11X12X13X14X15IX16X17LX18X19X20X21X22X23QQX24KN(EX26)n Formula III (X1X2X3)m-EX5X6X7X8X9EELEKKIEELLKKAEEQQKKN(EX26)n Formula IV (X1X2X3)m-EX5EKX8X9EELEKKIEELLKKAEEQQKKN(EX26)n Formula V wherein the definitions of X1, X2, X3, m, X4, X5, X6, X7, X8, X9, X10, X11, X12, X13, X14, X15, X16, X17, X18, X19, X20, X21, X22, X23, X24, X26 and are as defined in any one of claims 1 to 3.

5. LIPOPEPTIDE, according to any one of claims 1 to 3, characterized in that the lipophilic compound is cholesterol, fatty acid, dihydrosphingosine or vitamin E.

6. LIPOPEPTIDE, according to claim 5, Petition 870250105357, dated 11 / 18 / 2025, p. 157 / 171 5 / 10 characterized by cholesterol being cholesteryl hemisuccinate, 2-cholesteryl acetic acid, 2-cholesteryl propionic acid, 3-cholesteryl propionic acid, 2-cholesteryl butyric acid, 2-cholesteryl isobutyric acid, 3-cholesteryl butyric acid, 3-cholesteryl isobutyric acid, 4-cholesteryl butyric acid, 2-cholesteryl-valeric acid, 2-cholesteryl-isovaleric acid, 3-cholesteryl-valeric acid, 5-cholesteryl-valeric acid, 2-cholesteryl-caproic acid, 6-cholesteryl-caproic acid, 2-cholesteryl enanthic acid, 7-cholesteryl enanthic acid, 2-cholesteryl caprylic acid, 8-cholesteryl caprylic acid and bromoacetate cholesteryl; or the fatty acid is a fatty acid containing 8 to 20 carbon atoms.

7. LIPOPEPTIDE, according to claim 6, characterized in that the fatty acid containing 8 to 20 carbon atoms is palmitic acid or octadecanoic acid.

8. LIPOPEPTIDE, according to any one of claims 1 to 7, characterized in that the lipopeptide has an amino acid sequence selected from amino acid sequences as set forth in SEQ ID NO: 11-19.

9. POLYPEPTIDE or a variant thereof, characterized by comprising or consisting of a sequence represented by Formula I: (X1X2X3)mX4X5X6X7X8X9X10X11X12X13X14X15IX16X17LX18X19X20X21 X22X23QQX24X2 5N(EX26)n Formula I wherein X1 is T, E, S; X2 is W or a hydrophilic amino acid; X3 is E, M or Q; m is O or I; X4 is E, A or T; X5 is W or a hydrophilic amino acid; Petition 870250105357, of 11 / 18 / 2025, page 158 / 171 6 / 10 Xe is E or D; X7 is R, K or Q; X8 is E, K or A; X9 is L or I; X10 is E, N, or A; X11 is E or N; X12 is L or Y; X13 is E, T, or A; X14 is K, S, R, or A; X15 is K, L, R, or Q; X16 is E, H, T, or Y; X17 is E, S, R, or A; X18 is L or I; X19 is K, E, or R; X20 is K, E, Q, or A; X21 is A or S; X22 is E or Q; X23 is E, N, or I; X24 is K, E, or D; X25 is K or R; X26 is Q, E, R, A, or Y; n is 0 or 1; and the variant differs from the polypeptide from which the variant is derived only in the substitution of one or more amino acid residues, and retains the biological function of the polypeptide from which the variant is derived.

10. POLYPEPTIDE, according to claim 9, characterized by having one or more of the following features: - X1 is T or E; Petition 870250105357, dated 11 / 18 / 2025, page 159 / 171 7 / 10 - X2 is W, D, E, H, K, Q, R, S, T or Y; - X3 is E or M; - X4 is E; - X5 is W, D, E, H, K, Q, R, S, T or Y; - X6 is E; - X7 is R or K; - X8 is E or K; - X10 is E or N; - X11 is E; - X12 is L; - X13 is E or T; - X14 is K or S; - X15 is K or L; - X16 is E or H; - X17 is E or S; - X18 is L; - X19 is K or E; - X20 is K or E; - X21 is A; - X22 is E; - X23 is E or N; - X24 is K or E; - X25 is K; - X26 is Q.

11. POLYPEPTIDE, according to claim 9, characterized by having one or more of the following features: - X2 is W or Y, preferably Y; - X3 is E; Petition 870250105357, dated 11 / 18 / 2025, page 160 / 171 8 / 10 - X5 is W or Y, preferably Y; - X7 is K; - Xs is E or K; - Xio is E; - Xi3 is E; - Xi4 is K; - Xi5 is K; - Xi6 is E; - Xi7 is E; - Xi9 is K; - X2 is K; - X23 is E; - X24 is K.

12. POLYPEPTIDE, according to any one of claims 9 to 11, characterized in that the polypeptide is represented by Formula II, Formula III, Formula IV or Formula V, (X1X2X3)mX4X5X6X7X8X9X10X11X12X13X14X15lX16X17LX18X19X20X21X22X23QQX24KN(EX26)n Formula II (X1X2X3)mEX5X6X7X8X9X10X11X12X13X14X15lX16X17LX18X19X20X21X22X23QQX24KN(EX26)n Formula III (X1X2X3)m-EX5X6X7X8X9EELEKKIEELLKKAEEQQKKN(EX26)n Formula IV (X1X2X3)m-EX5EKX8X9EELEKKIEELLKKAEEQQKKN(EX26)n Formula V where the definitions of X1, X2, X3, m, X4, X5, X6, X7, X8, X9, X10, X11, X12, X13, X14, X15, X16, X17, X18, X19, X20, X21, X22, X23, X24, X26 and are, as per Petition 870250105357, dated 11 / 18 / 2025, pp. 161 / 171 9 / 10 defined in any of claims 9 to 11.

13. POLYPEPTIDE, according to any one of claims 9 to 11, characterized in that the lipopeptide has an amino acid sequence selected from amino acid sequences as set forth in SEQ ID NO: 21-29.

14. CONJUGATE, characterized by comprising the polypeptide or a variant thereof, as defined in any of claims 9 to 13, and a modification group.

15. ISOLATED NUCLEIC ACID, characterized by encoding the polypeptide or variant thereof, as defined in any one of claims 9 to 13.

16. VECTOR, characterized by comprising the isolated nucleic acid, as defined in claim 15.

17. HOST CELL, characterized by comprising the isolated nucleic acid, as defined in claim 15, and / or a vector comprising the isolated nucleic acid, as defined in claim 15.

18. MULTIMER, characterized by being formed with the lipopeptide or a salt, a solvate, a hydrate, a complex, a chelate, a non-covalent complex or a pharmaceutically acceptable prodrug thereof, as defined in any one of claims 1 to 8, or the polypeptide or a variant thereof, as defined in any one of claims 9 to 13.

19. COMPOSITION, characterized by comprising the lipopeptide or a salt, a solvate, a hydrate, a complex, a chelate, a non-covalent complex or a pharmaceutically acceptable prodrug thereof, as defined in any of claims 1 to 8, or the polypeptide or a variant thereof, as defined in any of claims 9 to 13, or a conjugate comprising the polypeptide or the Petition 870250105357, dated 11 / 18 / 2025, p. 162 / 171 10 / 10 variant thereof and a modification group, or an isolated nucleic acid encoding the polypeptide or a variant thereof, or a vector comprising the isolated nucleic acid, or a host cell comprising the isolated nucleic acid and / or the vector, or a multimer formed with the lipopeptide or a salt, a solvate, a hydrate, a complex, a chelate, a non-covalent complex or a pharmaceutically acceptable prodrug thereof or the polypeptide or a variant thereof.

20. USE OF THE LIPOPEPTIDE or of a salt, a solvate, a hydrate, a complex, a chelate, a non-covalent complex or a pharmaceutically acceptable prodrug thereof, as defined in any one of claims 1 to 8, or of the polypeptide or a variant thereof, as defined in any one of claims 9 to 13, or of the conjugate, as defined in claim 14, or of the multimer, as defined in claim 18, characterized in being in the manufacture of a pharmaceutical composition or a medicament, wherein the pharmaceutical composition or medicament is used as a viral membrane fusion inhibitor or to treat a viral infection or a disease caused by viral infection.

21. USE, according to claim 20, characterized in that the viral infection is an infection caused by a virus selected from the group consisting of HIV and a drug-resistant strain thereof, SARS-CoV-2 and a mutant strain thereof, MERS-CoV, EBOV, MARV, IAV, RABV and VSV.

22. USE, according to claim 21, characterized in that the viral infection is an infection caused by HIV or by a drug-resistant strain thereof. Petition 870250105357, dated 11 / 18 / 2025, pp. 163 / 171

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