key: cord-0898367-lref2wap
authors: Memariani, Hamed; Memariani, Mojtaba
title: Therapeutic and prophylactic potential of anti-microbial peptides against coronaviruses
date: 2020-04-18
journal: Ir J Med Sci
DOI: 10.1007/s11845-020-02232-4
sha: 2b001d2798aa0372689608f446d79007b29169f5
doc_id: 898367
cord_uid: lref2wap

nan

resistance development, AMPs seem to be ideal drug leads for treating various infections including viral diseases [5] .

In an attempt to appraise anti-viral activity of mouse βdefensin-4-derived peptides, Zhao et al. [6] found that a short peptide named P9 lessened in vitro infectivity of MERS-CoV (strain hCoV-EMC/2012) or SARS-CoV (strain HKU398490) at non-toxic concentrations, ranging from 0.4 to 50 μg/mL. In this context, more than 95% inhibition of viral infectivity was observed at concentrations above 25 μg/mL. Interestingly, both liquid and powder forms of P9 still retained their anti-viral potency, even after 1 year of storage at − 20°C. In terms of anti-viral modes of action, P9 penetrated into cells together with viruses through endocytosis and repressed endosomal acidification, thereby prohibiting membrane fusion and subsequent viral genome release. Western blot assay also revealed that P9 bound to S2 of MERS-CoV spike glycoprotein [6] , a subunit involving in viral membrane fusion and entrance into the host cell. Thus, P9 can thwart cellular entry of MERS-CoV by direct interaction with spike glycoprotein. Another study deciphered a concentration-related inactivation of SARS-CoV pseudovirus by Mucroporin-M1, an analogue peptide of Mucroporin retrieved from the venom of scorpion Lychas mucronatus [3] . The 50% inhibitory concentrations of Mucroporin-M1 against SARS-CoV pseudovirus and HeLa-ACE2 cell were 14.46 and 61.58 μg/mL, respectively, leading to a selectivity index of 4.26. This finding indicated that anti-SARS-CoV activity of Mucroporin-M1 did not arise from cytotoxic effects of the peptide. Strikingly, incubation of SARS-CoV with 20 μg/mL of Mucroporin-M1 for 1 h could almost extinguish viral infectivity [3] . It is assumed that virucidal effects of Mucroporin-M1 may be due to direct interaction of the peptide with the viral envelope.

Beyond direct anti-viral effects, some AMPs are capable of regulating expression levels of several genes involved in innate and adaptive immunity toward viral antigens. In macrophage-like THP-1 cells, 1 μg/mL of a recombinant protein consisting of human β-defensin (HBD) 2 and a receptorbinding domain of MERS-CoV S protein (S RBD) has been observed to augment in vitro expression levels of genes associated with innate immunity such as interferon-beta (IFN-β), IFN-γ, tumor necrosis factor-alpha (TNF-α), interleukin-1β (IL-1β), and IL-6 [4] . In another study, rhesus peptide θdefensin-1 (RTD-1) had no inhibitory activity on viral titers in vitro and in vivo [2] . However, RTD-1 mitigated pulmonary pathology, particularly necrotizing bronchiolitis, during the infection, mainly by alteration of cytokine responses to SARS-CoV in lung tissues. Based on these findings, it seems that some AMPs have the potential to alleviate severity of coronavirus diseases indirectly by reduction of pulmonary inflammation.

Regarding in vivo studies, some AMPs were able to protect mice against coronavirus-related pulmonary disease and mortality. For example, intranasal pre-treatment of BALB/c mice with two doses (5 mg/kg) of RTD-1 15 min before SARS-CoV infection followed by a single dose at 18 h postinfection led to 100% survival and little weight loss, whereas mortality rate of around 75% and obvious weight loss were observed in infected mice receiving no RTD-1 [2] . Of note, RTD-1-protected mice surviving a lethal dose of SARS-CoV showed neither signs of morbidity nor weight loss in future exposure. In the case of peptide P9, Zhao et al. [6] highlighted both preventive and therapeutic effects against SARS-CoV in BALB/c mice at day 3 post-infection. In this respect, one dose (100 μg/mouse) of intratracheal P9 for prophylaxis and 5 doses of intranasal P9 for therapy considerably decreased viral titers in lungs of mice challenged with SARS-CoV compared with SARS-CoV-infected untreated mice (P < 0.05).

AMPs have the potential to be exploited as vaccine adjuvants. For instance, Kim et al. [4] found that C57BL/6 mice immunized with 10 μg of the HBD 2-conjugated S RBD had significantly greater S RBD-specific immunoglobulin G levels in comparison with those receiving S RBD alone (P < 0.01). Likewise, sera of mice immunized with HBD 2conjugated S RBD efficiently inhibited the binding of S RBD to its receptor on Huh-7 cells [4] . These observations highlight the ability of AMP-conjugated proteins to elicit high neutralizing antibody titers.

Inhalation of AMPs as therapeutics or prophylactics represents an auspicious strategy for treatment of not only COVID-19 but also other coronavirus infections. We also envisage that conjugation of AMPs with aptamers or nanoparticles will offer undoubted advantages over AMPs alone. Last but not least, combination of AMPs with current anti-viral drugs may exert potent synergistic activities as well as minimizing the emergence of drug-resistant mutants. All in all, these data will pave the way for future clinical trials of AMPs for treatment of patients with viral respiratory diseases.

Q&A: the novel coronavirus outbreak causing COVID-19

Rhesus theta-defensin prevents death in a mouse model of severe acute respiratory syndrome coronavirus pulmonary disease

Virucidal activity of a scorpion venom peptide variant mucroporin-M1 against measles, SARS-CoV and influenza H5N1 viruses

Human β-defensin 2 plays a regulatory role in innate antiviral immunity and is capable of potentiating the induction of antigen-specific immunity

Melittin: a venom-derived peptide with promising anti-viral properties

A novel peptide with potent and broad-spectrum antiviral activities against multiple respiratory viruses

Authors' contributions Both authors contributed equally for writing and revision of this manuscript.

Conflict of interest The authors declare that they have no conflict of interest.Ethics approval This article does not contain any studies with human participants or animals performed by any of the authors.Consent for publication All authors approved the publication of the manuscript.