WO2022029810A1

WO2022029810A1 - Peptides able to bind angiotensin-converting enzyme 2 (ace2) and medical uses thereof

Info

Publication number: WO2022029810A1
Application number: PCT/IT2021/050235
Authority: WO
Inventors: Emanuele BELLACCHIO
Original assignee: Ospedale Pediatrico Bambino Gesu'
Priority date: 2020-08-07
Filing date: 2021-07-29
Publication date: 2022-02-10
Also published as: EP4192843A1; IT202000019708A1

Abstract

The present invention concerns peptides able to bind ACE2 and medical uses thereof, in the treatment and prevention of viral infections caused by viruses which exploit an interaction with ACE2 to enter in host cells, such as SARS-CoV-2, and of the diseases caused by said infections.

Description

PEPTIDES ABLE TO BIND ANGIOTENSIN-CONVERTING ENZYME 2 (ACE2) AND MEDICAL USES THEREOF ------ The present invention concerns peptides able to bind the angiotensin-converting enzyme 2 (ACE2) and medical uses thereof. In particular, the present invention concerns peptides able to bind ACE2 and medical uses thereof, in the treatment and prevention of viral infections caused by viruses which exploit an interaction with ACE2 to enter in host cells, such as SARS-CoV-2, and of the diseases caused by said infections. The severe acute respiratory syndrome coronavirus 2 (SARS-CoV- 2) was first identified in China on December 2019 and in few months became a worldwide threat that heavily conditioned the public health, social life and economy of nations. In the most severely affected patients, the infection is characterized by a devastating cytokine response, thrombosis and organ dysfunction (1-2). SARS-CoV, the predecessor of SARS-CoV-2, was firstly recognized also in China, in 2002, as responsible of the severe acute respiratory syndrome (SARS). In few months it had spread over other 30 countries (mostly Asian, e.g. Hong Kong, Singapore, Taiwan, Vietnam etc, with very few cases in Canada, United States and Europe) killing 10% ca. of the total of 8000 infected people. The eradication of SARS (last cases were reported in 2004) is believed to have been the result of measures essentially identical to those applied during the epidemics in the middle-age, such as the isolation of infected patients and the quarantine of whoever was known or suspected to have been in contact with infected persons. No drug specific for the virus has been made available during SARS-CoV outbreak nor in the years later, and all attempts to produce vaccines against SARS and the Middle East Respiratory Syndrome (MERS) failed. Studies on potential vaccines raised safety concerns after observing that they increase the risk of pulmonary immunopathology (3-6). Furthermore, vaccines do not warrant immunization against coronaviruses since these viruses are characterized by high mutation rates. Regarding SARS-CoV-2, several clinical trials are underway for the treatment of coronavirus disease 2019 (COVID-19). Among these, the plasma therapy (also named convalescent plasma), which makes use of the plasma obtained from recovered donors, and previously used with success in the treatment of SARS, MERS, and the H1N1 pandemic in 2009, showed excellent results on severely ill covid-19 patients (7). Various pharmacological treatments are also under investigation for different phases of the disease, which imply antiviral drugs, and drugs or antibodies capable to reduce the abnormal excessive immunological reactions responsible of organ damages (8). These treatments consist of substances repurposed from other diseases, which can speed up the search of therapeutic options since their mechanisms of action and toxicity profiles are at least partially known. Regarding antivirals, a common drawback for these drugs is represented by the severe side effects and the fact that they can induce viral resistance. In particular, given the characteristics of high mutation and infection rates of SARS-CoV-2, it can be envisaged that the clinical utility of therapeutic approaches based on drugs specifically targeting SARS- CoV-2 molecular components might be spoiled by rapidly emerging resistant strains. Furthermore, it remains the intrinsic difficulty to produce new and efficient antivirals. This is also evident by the fact that to date no new antiviral drug has been made for the specific neutralization of SARS- CoV-2 nor for its predecessor, SARS-CoV, despite almost two decades passed after the first appearance of the older virus. After all, the old and new coronaviruses present the same mechanism of infection. The SARS-CoV-2 genome shares about 80% sequence identity with SARS-CoV. In addition, the spike glycoprotein, located on the virus surface, is exploited by both viruses to attach themselves to the same host cell receptor that is the angiotensin-converting enzyme 2 (ACE2) (9-10), and to mediate the fusion of the viral and cellular membranes (11-12). Thus, the interaction between the spike and ACE2 proteins is crucial for the virus to gain access into cells and to start its replication. Even if SARS-CoV-2 pandemic will cease naturally, without drugs specifically blocking this type of viruses we will remain almost unprepared if another dangerous virus variant will emerge in the future. Therefore, it will be highly valuable to pave the way to pharmacological strategies that target efficiently and specifically SARS-CoV-2 and other members of the betacoronavirus family. In the light of the above, it is therefore apparent the need to provide new compounds for the treatment and the prevention of infections and diseases caused by coronaviruses, in particular by SARS-CoV-2, which are able to overcome the disadvantages of known therapies. According to the present invention, small peptides have now been found, which are comprised in specific amino acid motifs and are able to bind the angiotensin-converting enzyme 2 (ACE2) with high affinity and to antagonize the interaction of this protein with the spike proteins of viruses. In particular, the small peptides of the present invention bind ACE2 with high affinity at a site that overlaps with the ACE2 region that interacts with the spike protein. Therefore, the peptides according to the present invention are able to block the interaction of SARS-CoV-2, SARS-CoV and human coronavirus NL63 (HCoV-NL63), as the peptides and the viruses bind to overlapping regions in the ACE2 receptor. In addition, the peptides of the present invention can also block other viruses that exploit the ACE2 receptor to enter in host cells. On the basis of the above, the peptides according to the present invention represent a pharmacological treatment against SARS-CoV-2 and other viruses that exploit the interactions with the ACE2 receptor to enter in host cells. The peptides according to the present invention are advantageously able to stop the infection at the early stage, by preventing viruses to enter into cells. In addition, the peptides according to the invention exert their antiviral function extracellularly. Therefore, low concentrations of the peptides can be used and the peptides need not to be cell-permeable. This implies that the peptides according to the present invention can have low toxicity profiles. As mentioned above, the peptides according to the present invention are able to bind ACE2, in addition to stopping any virus that exploit an interaction with the ACE2 receptor to enter in host cells (to date, SARS-CoV, SARS-CoV-2, and human coronavirus NL63 (HCoV-NL63)). Moreover, the peptides according to the present invention can be used as antiviral drugs against virus variants (whether old or new viruses) that bind the ACE2 receptor within or near the overlapping region mentioned above. Therefore, differently from conventional treatments based on antiviral drugs or vaccines, the peptides of the present invention can exert their antiviral effect also against virus variants deriving from mutation(s) of the virus. A further advantage of the peptides according to the present invention is that they are designed to allow easy attachment of various chemical groups at their extremities (especially at the N-terminus) without affecting their capability to bind ACE2. In addition, the peptides of the invention are characterised by an intramolecular disulphide, which leads to the formation of cyclic peptides and confers the peptides with a conformation suitable for the binding to ACE2. Analogous cyclization to those made with an intramolecular disulphide can be obtained by exploiting other suitable chemical conjugations between amino acids, which are known from the state of the art. Moreover, the efficiency of these peptides in antagonizing the spike-ACE2 interaction can be modified by chemically attaching suitable bulky groups (as known from the state of the art) to produce the desired steric hindrance within or near the ACE2 region targeted for binding by viral spike proteins. In addition, the modality with which these peptides are delivered (oral, systemic, sprayed into the respiratory airways, etc) or stabilized (to gain either resistance or susceptibility to the activity of proteases or to modifications by other enzymes) or targeted to desired tissues can be modified by attaching suitable chemical groups (as known from the state of the art). The peptides of the present invention are designed to target a particular region of ACE2 that is relatively small, flat and surrounded by a number of glycosylation sites. These features have so far made difficult to pharmacologically target this region of ACE2 with drugs for antiviral and other purposes. The possibility to have drugs that bind to this new region opens new avenues also for the pharmacological regulation of ACE2 activity. Therefore, in addition to antiviral uses, the ability of these peptides to physically bind ACE2 could also be used to pharmacologically protect/stabilize this protein in order to sustain higher ACE2 enzymatic activity since this is desirable in certain conditions. In fact, enhanced ACE2 activity has been shown to be protective in cardiovascular diseases (14- 17), diabetes (18), liver and renal damage (19-20), and lung failure (21- 22). The beneficial effects of an induced increase of ACE2 activity have been demonstrated for various pathologies by using recombinant enzyme ACE2 and small-molecule activators (23), and ACE2-like enzyme obtained from bacteria (24). It is therefore specific object of the present invention a peptide able to bind angiotensin-converting enzyme 2, said peptide comprising or consisting of the following amino acid motif:

Motif I, in particular

Motif I-b. According to the present invention, the peptide can comprise or consist of one of the following amino acid motifs:

Motif II or

Motif III According to an embodiment of the present invention, the peptide can comprise or consist of the following amino acid motif

Motif II-b The motifs are written by the syntax of Prosite (25). Specifically, the square bracket indicates that the position is occupied by one of the amino acids listed in the same bracket, "x" represents any amino acid, and the parenthesis on the right of an amino acid indicates how many times that amino acid is repeated. The possible stereoisomeric L- or D-form at specific positions is indicated below the motif; “L/D" means that the particular amino acid can be either in L- or D-form. In particular, the peptide according to the present invention is able to bind on the region of residues Asp30, Asn33, His34, Glu37, Gly319, Leu320, Pro321, Thr324, Lys353, Gly354, Phe356, Met383, Ala384, Ala386, Ala387, Gln388, Pro389, Arg393, Phe555, Arg559 of angiotensin- converting enzyme 2. According to specific embodiments of the present invention, the peptide comprising or consisting of the amino acid motif II and motif II-b can comprise or consist of a sequence chosen from the group consisting of Gln-Cys-Tyr-Met-Cys-D-Ser-D-Val-Tyr (SEQ ID NO:1), Lys-Cys-Tyr- Met-Cys-D-Ser-Val-Tyr (SEQ ID NO:2), Lys-Cys-Tyr-Met-Cys-D-Glu-Val- Tyr (SEQ ID NO:3) and Lys-Cys-Tyr-Leu-Cys-D-Glu-Ala-Tyr-Gly-Val (SEQ ID NO:4), preferably SEQ ID NO:1, or combination thereof. The peptides of sequences SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:3 and SEQ ID NO:4 are herewith also named SG2, SG1, SG3 and SG4, respectively. They can be represented as follows:

(SEQ ID NO:2)

(SEQ ID NO:1)

(SEQ ID NO:3)

(SEQ ID NO:4) As mentioned above, small peptides SG1, SG2, SG3, and SG4 have a high affinity binding to the human ACE2 at sites of this receptor overlapping with the binding regions exploited by SARS-CoV, SARS-CoV- 2, and HCoV-NL63 in their interaction with host cells. The lines connecting the two cysteines represent an intramolecular disulphide bond (S-S). The intramolecular disulphide bond can be formed between the two cysteines of the peptides. This disulphide bond confers the peptides with a conformation suitable for the binding to ACE2. Also, the intramolecular disulphide bond causes molecular cyclization, which increases the stability of peptides. The disulphide bond can be formed either prior to the use of the peptides, or also during their use. In fact, disulphide bonds form spontaneously in oxidizing redox conditions, for example in the blood plasma (13). Therefore, the intramolecular disulphide bond in these peptides can form also after administration of the peptides to patients. This reaction is particularly likely to occur since the peptides contain two proximal cysteines and are exposed to oxidative conditions in the extracellular micro-environment where ACE2, the designed target of the peptides, is localized. The peptides are designed to bind ACE2 in the region shown in Figure 1. According to the present invention, the combinations of the peptides of sequences SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:3 and SEQ ID NO:4 can be for example: SEQ ID NO:1 and SEQ ID NO:2; SEQ ID NO:1 and SEQ ID NO:3; SEQ ID NO:1 and SEQ ID NO:4; SEQ ID NO:2 and SEQ ID NO:3; SEQ ID NO:2 and SEQ ID NO:4; SEQ ID NO:3 and SEQ ID NO:4; SEQ ID NO:1, SEQ ID NO:2 and SEQ ID NO:3; SEQ ID NO:1, SEQ ID NO:3 and SEQ ID NO:4; SEQ ID NO:1, SEQ ID NO:2 and SEQ ID NO:4; SEQ ID NO:2, SEQ ID NO:3 and SEQ ID NO:4; SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:3 and SEQ ID NO:4. The above mentioned peptides SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:3 and SEQ ID NO:4 are identified by motif I and II. According to the present invention, the peptide comprising or consisting of the amino acid motif I can comprise or consist of a sequence chosen from the group consisting of Gln-Cys-Tyr-Gly-Cys-D-Ala-D-Ala- Tyr (SEQ ID NO:9), Gln-Cys-Tyr-Gly-Cys-D-Val-D-Val-Tyr (SEQ ID NO:10), Lys-Cys-Tyr-Asp-Cys-D-Ser-Val-Tyr (SEQ ID NO:20), Lys-Cys- Tyr-Gln-Cys-Gln-Tyr-Tyr (SEQ ID NO:21), Lys-Cys-Tyr-Glu-Cys-D-Ser- Val-Tyr (SEQ ID NO:22), Tyr-Glu-His-Cys-Tyr-Val-Cys-Glu-Thr-D-Tyr (SEQ ID NO:44) or combinations thereof. According to the present invention, the peptide comprising or consisting of the amino acid motif II can comprise or consist of a sequence chosen from the group consisting of D-Tyr-Gly-Asp-His-Cys-Tyr-Met-Cys- D-Asp-Val-D-Tyr (SEQ ID NO:7), D-Tyr-Gly-Asp-His-Cys-Tyr-Met-Cys-D- Asp-Val-Tyr(SEQ ID NO:8), Gln-Cys-Tyr-Met-Cys-D-Ser-Val-Tyr (SEQ ID NO:11), His-Cys-Tyr-Met-Cys-D-Ser-Ile-Tyr (SEQ ID NO:15), His-Cys-Tyr- Met-Cys-D-Ser-Met-Tyr (SEQ ID NO:16), His-Cys-Tyr-Met-Cys-D-Ser-Val- Tyr (SEQ ID NO:17), Lys-Cys-Tyr-Leu-Cys-D-Glu-Ala-Tyr-D-Ala-Ile (SEQ ID NO:23), Lys-Cys-Tyr-Leu-Cys-D-Glu-Ala-Tyr-D-Ala-Val (SEQ ID NO:24), Lys-Cys-Tyr-Leu-Cys-D-Glu-Val-Tyr-Gly-Val (SEQ ID NO:25), Lys-Cys-Tyr-Leu-Cys-D-Glu-Val-Tyr-Ile (SEQ ID NO:26), Lys- Cys-Tyr-Leu-Cys-D-Ser-Leu-Tyr (SEQ ID NO:27), Lys-Cys-Tyr-Met- Cys-D-Glu-D-Val-Tyr (SEQ ID NO:28), Lys-Cys-Tyr-Met-Cys-D-Ser-Leu- Tyr (SEQ ID NO:30), Tyr-Asp-His-Cys-Tyr-Met-Cys-D-Asp-Ala-D-Tyr (SEQ ID NO:34), Tyr-Asp-His-Cys-Tyr-Met-Cys-D-Asp-Ala-Tyr (SEQ ID NO:35), Tyr-Asp-His-Cys-Tyr-Met-Cys-D-Asp-D-Met-D-Tyr (SEQ ID NO:36), Tyr-Asp-His-Cys-Tyr-Met-Cys-D-Asp-D-Met-Tyr (SEQ ID NO:37), Tyr-Asp-His-Cys-Tyr-Met-Cys-D-Asp-Met-Tyr (SEQ ID NO:38), Tyr-Asp- His-Cys-Tyr-Met-Cys-D-Ser-Met-Tyr (SEQ ID NO:39), Tyr-Glu-His-Cys- Tyr-Met-Cys-Asp-D-Met-Tyr (SEQ ID NO:40), Tyr-Glu-His-Cys-Tyr-Met- Cys-Glu-Thr-D-Tyr (SEQ ID NO:41), Tyr-Glu-His-Cys-Tyr-Thr-Cys-D-Ala- Ile-D-Tyr (SEQ ID NO:42), Tyr-Glu-His-Cys-Tyr-Thr-Cys-Glu-Ile-D-Tyr (SEQ ID NO:43), Tyr-Gly-Asp-His-Cys-Tyr-Met-Cys-D-Ser-Met-Tyr (SEQ ID NO:45), Tyr-Gly-Glu-His-Cys-Tyr-Met-Cys-Asp-Val-Tyr (SEQ ID NO:46) or combinations thereof. According to the present invention, the peptide comprising or consisting of the amino acid motif III can comprise or consist of a sequence chosen from the group consisting of D-Tyr-Glu-His-Cys-Tyr-Met- Cys-Ser-Asp-D-Met-Tyr (SEQ ID NO:6), Glu-His-Cys-Tyr-Met-Cys-Ser-Asp-Ala-Tyr (SEQ ID NO:12), Glu-His-Cys-Tyr-Met-Cys-Ser-Glu-Val-Tyr (SEQ ID NO:13), Gly-Gly-Gly-Glu-His-Cys-Tyr-Met-Cys-Ser-Asp-D-Met-Tyr (SEQ ID NO:14), Ser-Ser-His-Cys-Tyr-Met-Cys-Gln-Glu-Val-Tyr (SEQ ID NO:33) or combinations thereof. According to an embodiment of the present invention, ACE2- binding small peptides can be modified by addition of linkers and chemical groups (from the state of the art) in order to modify critical properties and functions of the peptides (stability, localization, capability to interfere with the binding of viral spike proteins to ACE2, capability to modulate ACE2 function, etc). For example the peptides of the present invention can be bound to a suitable bulky group to produce the desired steric hindrance within or near the ACE2 region targeted for binding by viral spike proteins, for example polyethylene glycol (PEG), or whichever group or even peptide sequence that can provide steric hindrance, or FITC, can be linked to chemical groups for delivery mode, to augment in vivo solubility (for example PEG or hydrophilic peptide sequences), stability (for example PEG, albumin, or albumin-binding peptides and in this latter case the peptides of the present invention can attach themselves spontaneously and in vivo to the albumin of patients after they have been administered), for targeting specific sites (for example albumin is known to preferentially accumulate at sites of inflammation, which is a condition characterizing SARS-CoV-2 infection), and for adding a capability to modulate ACE2 function. Therefore, the peptide according to the present invention can be linked, preferably at the N-terminus, to one or more functional chemical groups chosen from the group consisting of polyethylene glycol (PEG), FITC, albumin or albumin-binding peptides. According to the present invention, the peptide can be linked to said one or more functional chemical group by one or more linker, such as - Ahx-Lys-Gly-Gly-Gly or Lys-Gly-Gly-Gly (SEQ ID NO:47), - (Gly)n wherein n can be a number ranging from 1 to 10, - (Gly-Ala)n wherein n can be a number ranging from 1 to 5 and the alanine residue can be in any of the stereochemical L- or D-form, - (Gly-Ser)n wherein n can be a number ranging from 1 to 5 and the serine residue can be in any of the stereochemical L- or D-form, - a sequence cleavable by the peptidase domain of ACE2 such as those fulfilling the consensus motif Pro-Xaa(1-3)-Pro+(hydrophobic/basic), wherein Xaa(1-3) can be any stretch of amino acids (with length from 1 to 3 amino acids), the sign “+” represents the cleavable bond, and the C- terminus can be either a hydrophobic or a basic residue. Sequences identified by such motif and additional sequences known to be cleavable by ACE2 are for example Asp-Arg-Val-Tyr-Ile-His-Pro-Phe-His+Leu (SEQ ID NO:48), Asp-Arg-Val-Tyr-Ile-His-Pro+Phe (SEQ ID NO:49), Gln-Arg- Pro-Arg-Leu-Ser-His-Lys-Gly-Pro-Met-Pro+Phe (SEQ ID NO:50), Tyr-Pro- Phe-Val-Glu-Pro+Ile (SEQ ID NO:51), Pro-Pro-Gly-Phe-Ser-Pro-Phe+Arg (SEQ ID NO:52), Tyr-Gly-Gly-Phe-Leu-Arg-Arg-Ile-Arg-Pro-Lys-Leu+Lys (SEQ ID NO:53), Ala-Pro+Lys (SEQ ID NO:54), Tyr-Val-Ala-Asp-Ala- Pro+Lys (SEQ ID NO:55), Gln-Leu-Tyr-Glu-Asn-Lys-Pro+Arg (SEQ ID NO:56), Arg-Pro-Pro-Gly-Phe-Ser-Pro+Phe (SEQ ID NO:57), Lys-Arg-Pro- Pro-Gly-Phe-Ser-Pro+Phe (SEQ ID NO:58). The utility of adding a linker cleavable by ACE2 can be that the conjugation of the peptides with other groups might be helpful for stabilization or localization purposes but in the same time this might decrease their affinity for ACE2. In such cases, it would be preferable that the ACE2-binding portion of the peptides becomes more solvent-exposed hence more available for the binding to ACE2 only after the conjugated peptides encounter the cells expressing ACE2, which are the locations where these peptides are most needed. This can be achieved by exploiting linkers cleavable by the ACE2 peptidase domain. The present invention concerns also a pharmaceutical composition comprising or consisting of a peptide as defined above, in combination with one or more excipients and/or adjuvants pharmaceutically acceptable. The pharmaceutical composition according to the present invention can further comprise one or more of a drug chosen from the group consisting of an anti-inflammatory drug, such as Tocilizumab (monoclonal antibody that acts as an interleukin 6 (IL-6) receptor antagonist) and analogues like Sarilumab (monoclonal antibody that works by inhibiting the interleukin-6 (IL-6)), Anakinra (interleukin-1 inhibitor), Baricitinib (Janus kinase inhibitor), Eculizumab (monoclonal antibody against complement C5), Emapalumab (monoclonal antibody against interferon gamma); an antimalarial drug, such as Hydroxychloroquine (which is also anti- inflammatory); an antibiotic drug, such as Azithromycin; an antiviral drug, such as Remdesivir (nucleotide analogue prodrug with broad antiviral activity), Lopinavir and Ritonavir (virus protease inhibitors that are used in combination), Interferons (cytokines with antiviral activity); an anticoagulant drug, such as Heparin. In addition, the present invention concerns a peptide as defined above, or pharmaceutical composition as defined above for medical use. The present invention concerns also a peptide as defined above or pharmaceutical composition as defined above for use in the treatment and prevention of a viral infection and/or a disease, which are caused by a virus able to enter in host cells by ACE2. Said virus can be a coronavirus, such as for example an alphacoronavirus, such as HCoV-NL63, or a betacoronavirus, such as SARS-CoV-2 or SARS-CoV, preferably a betacoronavirus, more preferably SARS-CoV-2. According to the present invention, the above-mentioned disease can be severe acute respiratory syndrome, preferably COVID-19. The peptide or the pharmaceutical composition according to the present invention can be administered systemically (orally, intravenously, or subcutaneously) or by spraying it into the respiratory airways. According to a further embodiment, the present invention concerns the peptide or the pharmaceutical composition as defined above for use as allosteric ACE2 activator for the prevention and treatment of a disease in which this activation is needed. For example, said disease can be a cardiovascular disease, diabetes, liver and renal damage or lung failure. ACE2 activators, by binding the protein surface at positions distant from the catalytic site and by also blocking the hinge movements of the two catalytic sub-domains to favour a substrate cleavage competent conformation, lock the enzyme in an active state. The present invention concerns also a combination of a peptide as defined above with one or more of a drug for separate or sequential use in the treatment and prevention of a viral infection and/or a disease, which are caused by a virus able to enter in host cells by ACE2, wherein said drug is chosen from the group consisting of an anti-inflammatory drug, such as Tocilizumab (monoclonal antibody that acts as an interleukin 6 (IL- 6) receptor antagonist) and analogues like Sarilumab (monoclonal antibody that works by inhibiting the interleukin-6 (IL-6)), Anakinra (interleukin-1 inhibitor), Baricitinib (Janus kinase inhibitor), Eculizumab (monoclonal antibody against complement C5), Emapalumab (monoclonal antibody against interferon gamma); an antimalarial drug, such as Hydroxychloroquine (which is also anti-inflammatory); an antibiotic drug, such as Azithromycin; an antiviral drug, such as Remdesivir (nucleotide analogue prodrug with broad antiviral activity), Lopinavir and Ritonavir (virus protease inhibitors that are used in combination), Interferons (cytokines with antiviral activity); an anticoagulant drug, such as Heparin. According to present invention, “separate use” is understood as meaning the administration, at the same time, of the two compounds of the composition according to the invention in distinct pharmaceutical forms. “Sequential use” is understood as meaning the successive administration of the two compounds of the composition according to the invention, each in a distinct pharmaceutical form. According to the present invention, the virus can be a coronavirus, such as for example an alphacoronavirus, such as HCoV-NL63, or a betacoronavirus, such as SARS-CoV-2 or SARS-CoV, preferably a betacoronavirus, more preferably SARS-CoV-2. The above-mentioned disease can be severe acute respiratory syndrome, preferably COVID-19. The present invention now will be described by an illustrative, but not limitative way, according to preferred embodiments thereof, with particular reference to the examples and the enclosed drawings, wherein: Figure 1 shows the designed mode of binding of the small peptides (shown as SG1, SG2 in Figure 1A and SG3, SG4 in Figure 1B; the peptide N- and C-terminus are indicated) onto the ACE2 protein. The protein ACE2 structure has been obtained from the Protein Data Bank (PDB) entry 1R42, and subjected to MD simulations together with each bound peptide for all ACE2/peptide complexes. In Figure 1C is shown the crystal structure of the complex formed by the SARS-CoV-2 spike receptor-binding domain and ACE2 (from PDB 6M0J). All complexes are oriented to present same view with respect to the ACE2 protein. It can be seen that the designed binding region of each peptide overlaps with the binding region of the spike protein. Figure 2 shows the results of fluorescence microscopy experiments made to determine the colocalization of the SG1, SG2, SG3, and SG4 peptides with ACE2 in two different cells (Caco-2 and HepG2). To monitor their localization, these peptides had been labelled with FITC (green fluorescence) through a linker (Lys-Gly-Gly-Gly SEQ ID NO:47) as follows: FITC-Ahx-Lys-Gly-Gly-Gly-SG1, FITC-Ahx-Lys-Gly-Gly-Gly-SG2, FITC- Ahx-Lys-Gly-Gly-Gly-SG3, and FITC-Ahx-Lys-Gly-Gly-Gly-SG4. ACE2 localization was monitored by measuring the fluorescence of the Alexa Fluor 546-conjugated primary antibody against ACE2 (red fluorescence). (A) Results of the localization of ACE2 and the peptides in Caco-2 cells. (B) Results of the localization of ACE2 and the peptides in HepG2 cells. The bottom row displays the fluorescence images emitted by the antibody, the middle row displays the fluorescence images emitted by the peptides, and the top row displays the merged images (the combined fluorescence emitted by each peptide and the antibody) (arrows indicate the orange colour of fusion resulting from the merging of fluorescence images, implying co-localization of peptides with ACE2). The images of cells treated with PBS alone are shown in the first column (NT) and those treated with each peptide in the other columns (the used peptide is indicated on top of each column). Figure 3 shows the position of catalytic residues in unbound ACE2 (PDB 1R42), ACE2 in complex with SARS-CoV-2 spike receptor-binding domain (PDB 6M0J), and ACE2 in complex with peptides (SG1, SG2, SG3, and SG4 obtained from MD simulation snapshots recorded after MD equilibration). The catalytic residues are labelled on the unbound ACE2 structure. For selected pairs of catalytic residues their distances in Å are reported. It can be seen that catalytic residues contributed by the two ACE2 sub-domains are closer in ACE2 bound to SARS-CoV-2 spike receptor-binding domain, and also in ACE2 bound to peptides SG1, SG2, SG3, and SG4, with respect to the unbound ACE2 structure. EXAMPLE 1: Study of the capability of SG1, SG2, SG3 and SG4 peptides to interact with the ACE2 protein Materials and Methods Peptides Peptides were synthetized with a fluorescent label for fluorescence confocal microscopy experiments. To this purpose, peptides SG1, SG2, SG3, and SG4 were conjugated at the N-terminus with the fluorescent group fluorescein isothiocyanate (FITC) through the 6-amino hexanoic acid (NH2-CH2-CH2-CH2-CH2-CH2-COOH) spacer (Ahx) and an additional tetrapeptide (Lys-Gly-Gly-Gly SEQ ID NO:47) linker to increase the distance of the fluorophore from the peptide residues that bind ACE2 (to avoid possible interferences with the binding). In each peptide an intramolecular disulphide bond between the two cysteines was formed. These modified peptides were obtained from the custom peptide synthesis service of D.B.A. Italia/GenScript. The purity of the peptides has been determined by HPLC and certificated by provider as follows: FITC-Ahx- Lys-Gly-Gly-Gly-SG1, 98.8%; FITC-Ahx-Lys-Gly-Gly-Gly-SG2, 90.7%, FITC-Ahx-Lys-Gly-Gly-Gly-SG3, 99.1%; FITC-Ahx-Lys-Gly-Gly-Gly-SG4, 99.3%. Determination of the cellular localization of the ACE2 receptor, of the peptides, and colocalization of the peptides with ACE2 by immunofluorescence Caco-2 cells from human colorectal adenocarcinoma and human hepatocarcinoma HepG2 cells employed in this experiment were purchased from ATCC (American Tissue Culture Collection). The cells have been cultured as indicated by ATCC. In particular, Caco-2 cells were maintained in culture medium DMEM (Dulbecco's Modified Eagle Medium)/F12 added with Foetal Bovine Serum (FBS) at 10% and with antibiotics (mixture of streptomycin and penicillin); HepG2 cells were maintained in culture with DMEM medium added with FBS at 10% e antibiotics (mixture of streptomycin and penicillin). The utilized media and complements were all purchased from Gibco (Thermofisher Scientific Italia). Both cellular types were amplified for the experiment in conditions of standard culture (incubated at 37°C, 5% of CO2, with humidity ca. 95%). For the experiment, cells were seeded at density of 10000 cells/well in 8-well chamber slide and fixed in cold acetone for 10 minutes at room temperature. Subsequently, the slides were subjected to two washings with PBS (Phosphate-buffered saline) purchased from Gibco (Thermofisher Scientific Italia), and then exposed for 20 minutes at various treatments at room temperature. The treatments included PBS alone (NT), and, separately, each of the following FITC-labeled peptides (each at concentration 5μM in PBS): FITC-Ahx-Lys-Gly-Gly-Gly-SG1, FITC-Ahx-Lys-Gly-Gly-Gly-SG2, FITC-Ahx-Lys-Gly-Gly-Gly-SG3, FITC-Ahx-Lys-Gly-Gly-Gly-SG4, wherein FITC is a fluorophore, which can be replaced by any other desired chemical group; Ahx-Lys-Gly-Gly-Gly is a spacer or linker (Lys- Gly-Gly-Gly SEQ ID NO:47); SG1, SG2, SG3 and SG4 are the above mentioned peptides of sequence SEQ ID NO:2, SEQ ID NO:1, SEQ ID NO:3 and SEQ ID NO:4, respectively. SG1, SG2, SG3 and SG4 represent the ACE2-binding region. The above mentioned FITC-labeled peptides can be represented as follows:

(Lys-Gly-Gly-Gly-Lys-Cys-Tyr-Met-Cys-D-Ser-Val-Tyr (SEQ ID NO:59); Lys-Gly-Gly-Gly-Gln-Cys-Tyr-Met-Cys-D-Ser-D-Val-Tyr (SEQ ID NO:60); Lys-Gly-Gly-Gly-Lys-Cys-Tyr-Met-Cys-D-Glu-Val-Tyr (SEQ ID NO:61); Lys-Gly-Gly-Gly-Lys-Cys-Tyr-Leu-Cys-D-Glu-Ala-Tyr-Gly-Val (SEQ ID NO:62)). At the end of 20 minutes, 3 consecutive washings in PBS of 5 minutes each. At the end of this series of washings, the slides were incubated for 1 hour at room temperature with a primary antibody against ACE2 (Angiotensin-converting enzyme 2). The antibody, conjugated with Alexa-Fluor546, was purchased from Santa Cruz Biotechnology and diluted 1:100 in PBS and Bovine Serum Albumin (BSA, from Gibco) at 0.5%. At the end of exposure, the slides were subjected to another series of 3 washings with PBS (each washing for 5 minutes) and finally subjected to staining of nuclei with DAPI (4′,6-diamidino-2-phenylindole) diluted 1:5000 in PBS. At the end of nuclear staining the slides were washed in PBS and mounted with a mixture of PBS and glycerol at 1:1 ratio. Fluorescence microscopy images were acquired and analysed with the confocal microscope Olympus FluoView FV1000 with 60x objective and FV10-ASW software (version 2.0). Molecular Dynamics simulations and determination of the binding affinity To determine the binding affinity of peptides to ACE2, the following procedure was made. Modelled peptide structures were individually posed onto ACE2 protein structure (ACE2 from Protein Data Bank, PDB, entry 1R42) employing a binding mode close to the expected docking (reminding that peptides were specifically designed with the purpose to fulfil characteristics of affinity, based on geometry and type of interacting atoms, for the chosen target region on ACE2). The peptides were initially posed without causing any atomic clash with ACE2 to avoid possible generation of artifacts in structural stability that could bias the conformational sampling during MD simulations. Thus, in their initial poses, the peptides were bound only loosely to ACE2 so that during simulations they could either bind more tightly to ACE2 (depending on affinities and correctness of the designed docking) or dissociate from this receptor. Dissociation was particularly possible because the region of ACE2 that the peptides were designed to target is on the protein surface and has a quite flat shape (Figure 1) (i.e. the targeted binding region on ACE2 does not consist of a protein cavity inside which the peptides could remain stably trapped for the difficulty in finding a path to escape outside). Molecular Dynamics (MD) simulations were performed using NAMD (v2.13) at temperature of 310.15 K in explicit water solvent at 0.1 ionic strength (by addition of Na⁺ and Cl- ions) with the Charmm36 force field inclusive of protein and sugar parameterizations (the original N- glycosylated groups, Zn²⁺ ion, and crystal water molecules as present in the ACE2 PDB crystal structure were all included in the simulations) employing a timestep 1.0 fs/step and flexible bonds, without restraining any atom. Before MD runs, two cycles of minimizations were carried (in the first cycle, the backbones of both protein and peptide were maintained fixed, letting to move only the side chains of ACE2 protein and of the peptide, water molecules, and ions; in the second cycle all atoms were minimized). After starting the MD simulations and achieving equilibration, the ACE2/peptide complexes from MD snapshots at 10 ns were used to determine the binding affinity of peptides towards ACE2. The ACE2/peptide complexes were employed as directly produced during MD simulations at 310.15 K (physiological temperature) without subjecting the structures to geometrical optimizations. The binding affinity of peptides and ACE2 was determined with the scoring function by Wang et al. (26). Results To verify that Caco-2 and HepG2 cells expressed the ACE2 receptor and to determine whether peptides colocalize with it (which is an indication that a physical interaction occurs between ACE2 and the peptides), the cells were treated as above, i.e. with PBS alone (NT) or with the individual peptides colored in green (FITC-Ahx-Lys-Gly-Gly-Gly-SG1, FITC-Ahx-Lys-Gly-Gly-Gly-SG2, FITC-Ahx-Lys-Gly-Gly-Gly-SG3, FITC- Ahx-Lys-Gly-Gly-Gly-SG4). As shown in Figure 2-A, Caco-2 cells express ACE2 receptor (in red), which is bound by all four peptides (as it can be seen with the orange colour (see arrows) of fusion resulting from the merging of fluorescence images) and, in particular, more quantitatively by the peptide FITC-Ahx-Lys-Gly-Gly-Gly-SG2. As shown in Figure 2-B, also HepG2 cells express the ACE2 receptor (in red), which is bound by all four peptides (orange fusion colour resulting from the merging of fluorescence images) (see arrows), and in particular more quantitatively by the peptides FITC-Ahx-Lys-Gly-Gly-Gly-SG2 and FITC-Ahx-Lys-Gly-Gly-Gly-SG3. The binding affinity, calculated as negative logarithm of the dissociation constant (pKd) on each ACE2/peptide complex obtained from MD snapshots yielded as results 9.74, 8.75, 10.60, and 8.55, respectively for peptides SG1, SG2, SG3, and SG4. EXAMPLE 2: Study of the capability of the peptides of the present invention to compete with the binding of SARS-CoV-2 Spike to ACE2 To determine the capability of peptides to compete with the binding of SARS-CoV-2 Spike to ACE2, the COVID-19 Spike-ACE2 Binding Assay Kit from RayBiotech was used (product code CoV-SACE2-1). This kit allows to determine the amount of ACE2/spike interaction and how it changes upon addition of potential competitors by measuring variations in optical absorbance. The essays were made using the FITC-labelled peptide (FITC-Ahx-Lys-Gly-Gly-Gly-SG1, FITC-Ahx-Lys-Gly-Gly-Gly-SG2, FITC-Ahx-Lys-Gly-Gly-Gly-SG3, and FITC-Ahx-Lys-Gly-Gly-Gly-SG4) one at a time at concentration of 10 micromolar. The results (expressed as percentage of the binding of the spike protein to ACE2 upon adding the peptides) were as follows: no added peptide, 100% ACE2/spike binding; FITC-Ahx-Lys-Gly-Gly-Gly-SG1, 99.7% ACE2/spike binding, FITC-Ahx- Lys-Gly-Gly-Gly-SG2, 39.5% ACE2/spike binding; FITC-Ahx-Lys-Gly-Gly- Gly-SG3, 91.0 ACE2/spike binding; FITC-Ahx-Lys-Gly-Gly-Gly-SG4, 88.60% ACE2/spike binding. Therefore, the last three peptides, and especially FITC-Ahx-Lys-Gly-Gly-Gly-SG2, caused a sensible reduction in the capacity of the spike protein to bind ACE2. However, it is important to note that a potential bias in this experiment might have caused to underestimate the ability of peptides SG1, SG2, SG3 and SG4 to inhibit the ACE2/spike-SARS-CoV-2 interaction. To explain this, it is first necessary to show how the employed assay works (the following text is extracted from the User Manual of the RayBio® COVID-19 Spike-ACE2 Binding Assay Kit I): “The RayBio® COVID-19 Spike-ACE2 binding assay uses a 96-well plate coated with recombinantly-expressed S-RBD. The testing reagent-of- choice is then added to the wells in the presence of recombinant human ACE2 protein. Unbound ACE2 is removed with washing, and a goat anti- ACE2 antibody is added that binds to the Spike-ACE2 complex. HRP- conjugated anti-goat IgG is then applied to the wells in the presence of 3,3’,5,5’-tetramethylbenzidine (TMB) substrate. The HRP-conjugated anti- goat IgG binds to the ACE2 antibody and reacts with the TMB solution, producing a blue color that is proportional to the amount of bound ACE2. The HRP-TMB reaction is halted with the addition of the Stop Solution, resulting in a blue-to-yellow color change. The intensity of the yellow color is then measured at 450 nm.” The spike-ACE2 binding assay in this example has been carried out on the same peptides investigated in the experiments of colocalization with ACE2 by confocal microscopy reported in example 1. Such peptides were synthesized bearing a conjugated fluorescein isothiocyanate (FITC) fluorophore. Since FITC has an absorption spectrum (with a maximum at 490 nm ca.) that partially overlaps with the absorbance at 450 nm monitored in the assay, possible partial retention of the peptides on the plates (and/or the coating material) might have caused additional absorbance at 450 nm. Any spurious contribution in absorbance by FITC opposes the decrease of the absorbance that in the assay is interpreted to be proportional to the amount of inhibition of the ACE2/spike interaction. This might have mistakenly caused the peptides to appear less efficient in this inhibition. EXAMPLE 3: Study of the capability of the peptides of the present invention to increase the enzymatic activity of the ACE2 receptor It has been recently found that the binding of SARS-CoV-2 increases the enzymatic activity of the ACE2 receptor (26). As for the mechanism allowing this enhancement of enzyme activity, by protein structural alignment the authors have evidenced that the interaction with the receptor binding domain of the spike protein of SARS-CoV-2 induces a hinge movement involving the two catalytic sub-domains of ACE2, which brings the catalytic residues mutually closer. This structural change has been proposed to energetically facilitate proteolysis of substrates by ACE2. The authors assessed such relative movement of sub-domains by measuring the angle formed by Asn137 on the rim of one sub-domain in the native ACE2 structure (PDB 1R42), the zinc atom at the catalytic centre, and Asn137 of superimposed ACE2 bound by the RBD of SARS- CoV-2 (PDB 6M0J), finding an increase of the angle by 5°. By performing this analysis on equilibrated conformers from the MD simulations (described above) of ACE2 protein complexed with peptides SG1, SG2, SG3, and SG4, it was found that the above angle, with respect to the native ACE2 structure (PDB 1R42) also increased: SG1, 3.73°; SG2, 7.6°; SG3, 11.7°; and SG4, 7.9°. This movement of sub-domains is also suggested by the following observation. Crystal structures show that the catalytic residues contributed by the two sub-domains of ACE2 are closer in the complex of the receptor with the spike protein of SARS-CoV-2 compared to the unbound ACE2, and the catalytic residues become also closer upon the binding of peptides of the present invention (SG1, SG2, SG3, and SG4) to ACE2 as observed with MD simulations (Figure 3). These results indicate that increased proximity of the two catalytic sub- domains can also be induced by the binding of these peptides. It is therefore plausible that the peptides of the present invention can stimulate ACE2 enzymatic activity in analogy with what has been experimentally observed with the binding of SARS-CoV-2 spike protein to ACE2. This can be based on a common effect of the ligands considering that the peptides are designed to bind a region of ACE2 that overlaps with the region targeted by the spike protein. Pharmacological enhancement of ACE2 enzymatic activity is desirable because it provides a protective function in a variety of diseases (14-22). References (1) Iba T, Levy JH, Levi M, Thachil J. Coagulopathy in COVID-19 [published online ahead of print, 2020 Jun 18]. J Thromb Haemost. 2020;10.1111/jth.14975. doi:10.1111/jth.14975. (2) Colling ME, Kanthi Y. COVID-19-associated coagulopathy: An exploration of mechanisms [published online ahead of print, 2020 Jun 19]. Vasc Med.2020;1358863X20932640. doi:10.1177/1358863X20932640. (3) Tseng CT, Sbrana E, Iwata-Yoshikawa N, et al. Immunization with SARS coronavirus vaccines leads to pulmonary immunopathology on challenge with the SARS virus. PLoS One. 2012;7(4):e35421. doi:10.1371/journal.pone.0035421. (4) Bolles M, Deming D, Long K, et al. A double-inactivated severe acute respiratory syndrome coronavirus vaccine provides incomplete protection in mice and induces increased eosinophilic proinflammatory pulmonary response upon challenge. J Virol. 2011;85(23):12201-12215. doi:10.1128/JVI.06048-11. (5) Agrawal AS, Tao X, Algaissi A, et al. Immunization with inactivated Middle East Respiratory Syndrome coronavirus vaccine leads to lung immunopathology on challenge with live virus. Hum Vaccin Immunother. 2016;12(9):2351-2356. doi:10.1080/21645515.2016.1177688. (6) Lindsley AW, Schwartz JT, Rothenberg ME. Eosinophil responses during COVID-19 infections and coronavirus vaccination [published online ahead of print, 2020 Apr 25]. J Allergy Clin Immunol. 2020;S0091-6749(20)30569-8. doi:10.1016/j.jaci.2020.04.021. (7) Duan K, Liu B, Li C, et al. Effectiveness of convalescent plasma therapy in severe COVID-19 patients. Proc Natl Acad Sci U S A. 2020;117(17):9490-9496. doi:10.1073/pnas.2004168117. (8) Magro G. COVID-19: review on latest available drugs and therapies against SARS-CoV-2. Coagulation and inflammation cross- talking [published online ahead of print, 2020 Jun 19]. Virus Res. 2020;198070. doi:10.1016/j.virusres.2020.198070. (9) Li W, Moore MJ, Vasilieva N, et al. Angiotensin-converting enzyme 2 is a functional receptor for the SARS coronavirus. Nature. 2003;426(6965):450-454. doi:10.1038/nature02145. (10) Yan R, Zhang Y, Li Y, Xia L, Guo Y, Zhou Q. Structural basis for the recognition of SARS-CoV-2 by full-length human ACE2. Science. 2020;367(6485):1444-1448. doi:10.1126/science.abb2762. (11) Gallagher TM, Buchmeier MJ. Coronavirus spike proteins in viral entry and pathogenesis. Virology. 2001;279(2):371-374. doi:10.1006/viro.2000.0757. (12) Xu Y, Lou Z, Liu Y, et al. Crystal structure of severe acute respiratory syndrome coronavirus spike protein fusion core. J Biol Chem. 2004;279(47):49414-49419. doi:10.1074/jbc.M408782200. (13) Bellacchio E, McFarlane KL, Rompel A, Robblee JH, Cinco RM, Yachandra VK. Counting the number of disulfides and thiol groups in proteins and a novel approach for determining the local pKa for cysteine groups in proteins in vivo. J Synchrotron Radiat. 2001;8(3):1056-1058. doi:10.1107/s0909049500017210. (14) Kuba K, Imai Y, Penninger JM. Multiple functions of angiotensin-converting enzyme 2 and its relevance in cardiovascular diseases. Circ J.2013;77(2):301-308. doi:10.1253/circj.cj-12-1544. (15) Patel VB, Zhong JC, Grant MB, Oudit GY. Role of the ACE2/Angiotensin 1-7 Axis of the Renin-Angiotensin System in Heart Failure. Circ Res. 2016;118(8):1313-1326. doi:10.1161/CIRCRESAHA.116.307708. (16) Arendse LB, Danser AHJ, Poglitsch M, et al. Novel Therapeutic Approaches Targeting the Renin-Angiotensin System and Associated Peptides in Hypertension and Heart Failure. Pharmacol Rev. 2019;71(4):539-570. doi:10.1124/pr.118.017129. (17) Trask AJ, Groban L, Westwood BM, et al. Inhibition of angiotensin-converting enzyme 2 exacerbates cardiac hypertrophy and fibrosis in Ren-2 hypertensive rats. Am J Hypertens. 2010;23(6):687-693. doi:10.1038/ajh.2010.51. (18) Qaradakhi T, Gadanec LK, McSweeney KR, et al. The potential actions of angiotensin-converting enzyme II (ACE2) activator diminazene aceturate (DIZE) in various diseases. Clin Exp Pharmacol Physiol.2020;47(5):751-758. doi:10.1111/1440-1681.13251. (19) Sansoè G, Aragno M, Wong F. Pathways of hepatic and renal damage through non-classical activation of the renin-angiotensin system in chronic liver disease. Liver Int.2020;40(1):18-31. doi:10.1111/liv.14272. (20) Oudit GY, Liu GC, Zhong J, et al. Human recombinant ACE2 reduces the progression of diabetic nephropathy. Diabetes. 2010;59(2):529-538. doi:10.2337/db09-1218. (21) Imai Y, Kuba K, Rao S, et al. Angiotensin-converting enzyme 2 protects from severe acute lung failure. Nature. 2005;436(7047):112-116. doi:10.1038/nature03712. (22) Kuba K, Imai Y, Rao S, et al. A crucial role of angiotensin converting enzyme 2 (ACE2) in SARS coronavirus-induced lung injury. Nat Med.2005;11(8):875-879. doi:10.1038/nm1267. (23) Zhang YY, Yu Y, Yu C. Antifibrotic Roles of RAAS Blockers: Update. Adv Exp Med Biol. 2019;1165:671-691. doi:10.1007/978-981-13- 8871-2_33. (24) Minato T, Nirasawa S, Sato T, et al. B38-CAP is a bacteria- derived ACE2-like enzyme that suppresses hypertension and cardiac dysfunction. Nat Commun. 2020;11(1):1058. doi:10.1038/s41467-020- 14867-z. (25) Sigrist CJ, de Castro E, Cerutti L, et al. New and continuing developments at PROSITE. Nucleic Acids Res.2013;41 (Database issue): D344-D347. doi:10.1093/nar/gks1067 (26) Wang R, Liu L, Lai L, Tang Y. SCORE: A New Empirical Method for Estimating the Binding Affinity of a Protein-Ligand Complex. J. Mol. Model.1998; 4: 379-394. (26) Lu J, Sun PD. 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Claims

CLAIMS 1) Peptide able to bind angiotensin-converting enzyme 2, said peptide comprising or consisting of the following amino acid motif:

Motif I 2) Peptide according to claim 1, wherein said peptide comprises or consists of one of the following amino acid motifs:

Motif II or

Motif III 3) Peptide according to any one of claims 1-2, wherein said peptide comprises or consists of the following amino acid motif

Motif II-b 4) Peptide according to anyone of claims 1-3, wherein said peptide is able to bind on the region of residues Asp30, Asn33, His34, Glu37, Gly319, Leu320, Pro321, Thr324, Lys353, Gly354, Phe356, Met383, Ala384, Ala386, Ala387, Gln388, Pro389, Arg393, Phe555, Arg559 of angiotensin-converting enzyme 2. 5) Peptide according to anyone of claims 1-4, wherein the peptide comprising or consisting of the amino acid motif II and motif II-b comprises or consists of a sequence chosen from the group consisting of Gln-Cys- Tyr-Met-Cys-D-Ser-D-Val-Tyr (SEQ ID NO:1), Lys-Cys-Tyr-Met-Cys-D- Ser-Val-Tyr (SEQ ID NO:2), Lys-Cys-Tyr-Met-Cys-D-Glu-Val-Tyr (SEQ ID NO:3) and Lys-Cys-Tyr-Leu-Cys-D-Glu-Ala-Tyr-Gly-Val (SEQ ID NO:4), preferably SEQ ID NO:1, or combination thereof. 6) Peptide according to anyone of claims 1-4, wherein the peptide comprising or consisting of the amino acid motif I comprises or consists of a sequence chosen from the group consisting of Gln-Cys-Tyr-Gly-Cys-D- Ala-D-Ala-Tyr (SEQ ID NO:9), Gln-Cys-Tyr-Gly-Cys-D-Val-D-Val-Tyr (SEQ ID NO:10), Lys-Cys-Tyr-Asp-Cys-D-Ser-Val-Tyr (SEQ ID NO:20), Lys-Cys- Tyr-Gln-Cys-Gln-Tyr-Tyr (SEQ ID NO:21), Lys-Cys-Tyr-Glu-Cys-D-Ser- Val-Tyr (SEQ ID NO:22), Tyr-Glu-His-Cys-Tyr-Val-Cys-Glu-Thr-D-Tyr (SEQ ID NO:44) or combinations thereof. 7) Peptide according to anyone of claims 1-4, wherein the peptide comprising or consisting of the amino acid motif II comprises or consists of a sequence chosen from the group consisting of D-Tyr-Gly-Asp-His-Cys- Tyr-Met-Cys-D-Asp-Val-D-Tyr (SEQ ID NO:7), D-Tyr-Gly-Asp-His-Cys-Tyr- Met-Cys-D-Asp-Val-Tyr(SEQ ID NO:8), Gln-Cys-Tyr-Met-Cys-D-Ser-Val- Tyr (SEQ ID NO:11), His-Cys-Tyr-Met-Cys-D-Ser-Ile-Tyr (SEQ ID NO:15), His-Cys-Tyr-Met-Cys-D-Ser-Met-Tyr (SEQ ID NO:16), His-Cys-Tyr-Met- Cys-D-Ser-Val-Tyr (SEQ ID NO:17), Lys-Cys-Tyr-Leu-Cys-D-Glu-Ala-Tyr- D-Ala-Ile (SEQ ID NO:23), Lys-Cys-Tyr-Leu-Cys-D-Glu-Ala-Tyr-D-Ala-Val (SEQ ID NO:24), Lys-Cys-Tyr-Leu-Cys-D-Glu-Val-Tyr-Gly-Val (SEQ ID NO:25), Lys-Cys-Tyr-Leu-Cys-D-Glu-Val-Tyr-Ile (SEQ ID NO:26), Lys- Cys-Tyr-Leu-Cys-D-Ser-Leu-Tyr (SEQ ID NO:27), Lys-Cys-Tyr-Met- Cys-D-Glu-D-Val-Tyr (SEQ ID NO:28), Lys-Cys-Tyr-Met-Cys-D-Ser-Leu- Tyr (SEQ ID NO:30), Tyr-Asp-His-Cys-Tyr-Met-Cys-D-Asp-Ala-D-Tyr (SEQ ID NO:34), Tyr-Asp-His-Cys-Tyr-Met-Cys-D-Asp-Ala-Tyr (SEQ ID NO:35), Tyr-Asp-His-Cys-Tyr-Met-Cys-D-Asp-D-Met-D-Tyr (SEQ ID NO:36), Tyr-Asp-His-Cys-Tyr-Met-Cys-D-Asp-D-Met-Tyr (SEQ ID NO:37), Tyr-Asp-His-Cys-Tyr-Met-Cys-D-Asp-Met-Tyr (SEQ ID NO:38), Tyr-Asp- His-Cys-Tyr-Met-Cys-D-Ser-Met-Tyr (SEQ ID NO:39), Tyr-Glu-His-Cys- Tyr-Met-Cys-Asp-D-Met-Tyr (SEQ ID NO:40), Tyr-Glu-His-Cys-Tyr-Met- Cys-Glu-Thr-D-Tyr (SEQ ID NO:41), Tyr-Glu-His-Cys-Tyr-Thr-Cys-D-Ala- Ile-D-Tyr (SEQ ID NO:42), Tyr-Glu-His-Cys-Tyr-Thr-Cys-Glu-Ile-D-Tyr (SEQ ID NO:43), Tyr-Gly-Asp-His-Cys-Tyr-Met-Cys-D-Ser-Met-Tyr (SEQ ID NO:45), Tyr-Gly-Glu-His-Cys-Tyr-Met-Cys-Asp-Val-Tyr (SEQ ID NO:46) or combinations thereof. 8) Peptide according to anyone of claims 1-4, wherein the peptide comprising or consisting of the amino acid motif III comprises or consists of a sequence chosen from the group consisting of D-Tyr-Glu-His-Cys-Tyr- Met-Cys-Ser-Asp-D-Met-Tyr (SEQ ID NO:6), Glu-His-Cys-Tyr-Met-Cys-Ser-Asp-Ala-Tyr (SEQ ID NO:12), Glu-His-Cys-Tyr-Met-Cys-Ser-Glu-Val-Tyr (SEQ ID NO:13), Gly-Gly-Gly-Glu-His-Cys-Tyr-Met-Cys-Ser-Asp-D-Met-Tyr (SEQ ID NO:14), Ser-Ser-His-Cys-Tyr-Met-Cys-Gln-Glu-Val-Tyr (SEQ ID NO:33) or combinations thereof. 9) Peptide according to any one of claims 1-8, wherein said peptide is linked, preferably at the N-terminus, to one or more functional chemical groups chosen from the group consisting of polyethylene glycol (PEG), FITC, albumin or albumin-binding peptides. 10) Peptide according to claim 9, wherein said peptide is linked to said one or more functional chemical group by one or more linker, such as Ahx-Lys-Gly-Gly-Gly or Lys-Gly-Gly-Gly (SEQ ID NO:47), (Gly)n wherein n can be a number ranging from 1 to 10, (Gly-Ala)n wherein n can be a number ranging from 1 to 5 and the alanine residue can be in any of the stereochemical L- or D-form, (Gly-Ser)n wherein n can be a number ranging from 1 to 5 and the serine residue can be in any of the stereochemical L- or D-form, a sequence cleavable by the peptidase domain of ACE2 such as those fulfilling the consensus motif Pro-Xaa(1-3)-Pro+(hydrophobic/basic), wherein Xaa(1-3) is any stretch of amino acids with length from 1 to 3 amino acids, the sign “+” represents the cleavable bond, and the C- terminus can be either a hydrophobic or a basic residue, such sequences cleavable by ACE2 are for example Asp-Arg-Val-Tyr-Ile-His-Pro-Phe- His+Leu (SEQ ID NO:48), Asp-Arg-Val-Tyr-Ile-His-Pro+Phe (SEQ ID NO:49), Gln-Arg-Pro-Arg-Leu-Ser-His-Lys-Gly-Pro-Met-Pro+Phe (SEQ ID NO:50), Tyr-Pro-Phe-Val-Glu-Pro+Ile (SEQ ID NO:51), Pro-Pro-Gly-Phe- Ser-Pro-Phe+Arg (SEQ ID NO:52), Tyr-Gly-Gly-Phe-Leu-Arg-Arg-Ile-Arg- Pro-Lys-Leu+Lys (SEQ ID NO:53), Ala-Pro+Lys (SEQ ID NO:54), Tyr-Val- Ala-Asp-Ala-Pro+Lys (SEQ ID NO:55), Gln-Leu-Tyr-Glu-Asn-Lys-Pro+Arg (SEQ ID NO:56), Arg-Pro-Pro-Gly-Phe-Ser-Pro+Phe (SEQ ID NO:57), Lys-Arg-Pro-Pro-Gly-Phe-Ser-Pro+Phe (SEQ ID NO:58). 11) Pharmaceutical composition comprising or consisting of a peptide as defined in any one of claims 1-10, in combination with one or more excipients and/or adjuvants. 12) Pharmaceutical composition according to claim 11, said pharmaceutical composition further comprising one or more of a drug chosen from the group consisting of an anti-inflammatory drug, such as Tocilizumab and analogues like Sarilumab, Anakinra, Baricitinib, Eculizumab, Emapalumab; an antimalarial drug, such as Hydroxychloroquine; an antibiotic drug, such as Azithromycin; an antiviral drug, such as Remdesivir, Lopinavir and Ritonavir, Interferons; an anticoagulant drug, such as Heparin. 13) Peptide as defined in any one of claims 1-10, or pharmaceutical composition as defined in any one of claims 11-12 for medical use. 14) Peptide as defined in any one of claims 1-10, or pharmaceutical composition as defined in any one of claims 11-12 for use in the treatment and prevention of a viral infection and/or a disease, which are caused by a virus able to enter in host cells by ACE2. 15) Peptide as defined in any one of claims 1-10 or pharmaceutical composition as defined in any one of claims 11-12, for use according to claim 14, wherein said virus is a coronavirus, such as for example an alphacoronavirus, such as HCoV-NL63, or a betacoronavirus, such as SARS-CoV-2 or SARS-CoV, preferably a betacoronavirus, more preferably SARS-CoV-2. 16) Peptide as defined in any one of claims 1-10, or pharmaceutical composition as defined in any one of claims 11-12, for use according to any one of claims 14-15, wherein the disease is severe acute respiratory syndrome, preferably COVID-19. 17) Peptide as defined in any one of claims 1-10, or pharmaceutical composition as defined in any one of claims 11-12, for use according to any one of claims 14-16, wherein said peptide or pharmaceutical composition is administered systemically, for example orally, intravenously or subcutaneously, or by spraying it into the respiratory airways. 18) Peptide as defined in any one of claims 1-10, or pharmaceutical composition as defined in any one of claims 11-12 for use as allosteric ACE2 activator for the prevention and treatment of a disease in which ACE2 activation is needed. 19) Peptide as defined in any one of claims 1-10, or pharmaceutical composition as defined in any one of claims 11-12 for use according to claim 18, wherein said disease is chosen from the group consisting of cardiovascular disease, diabetes, liver and renal damage or lung failure. 20) Combination of a peptide as defined in any one of claims 1-10 with one or more of a drug for separate or sequential use in the treatment and prevention of a viral infection and/or a disease, which are caused by a virus able to enter in host cells by ACE2, wherein said drug is chosen from the group consisting of an anti-inflammatory drug, such as Tocilizumab and analogues like Sarilumab, Anakinra, Baricitinib, Eculizumab, Emapalumab; an antimalarial drug, such as Hydroxychloroquine; an antibiotic drug, such as Azithromycin; an antiviral drug, such as Remdesivir, Lopinavir and Ritonavir, Interferons; an anticoagulant drug, such as Heparin. 21) Combination according to claim 20, for use according to claim 20, wherein said virus is a coronavirus, such as for example an alphacoronavirus, such as HCoV-NL63, or a betacoronavirus, such as SARS-CoV-2 or SARS-CoV, preferably a betacoronavirus, more preferably SARS-CoV-2. 22) Combination according to any one of claims 20-21, for use according to any one of claims 20-21, wherein the disease is severe acute respiratory syndrome, preferably COVID-19.