Dermaseptins as potential antirabies compounds

Abstract

Over the last 20 years, natural peptides playing a key role in defense mechanisms and innate immunity have been isolated from unicellular organisms. Amphibian skin secretes dermaseptins, 24-34 amino acids in length that have a wide antimicrobial spectrum incorporating yeast, fungi, protozoa, bacteria and enveloped viruses. The anti-rabies virus (RABV) activity of dermaseptins S3 (30aa) and S4 (28aa) from Phyllomedusa sauvagei has been investigated, and further dissected its molecular basis by comparing punctual mutation or deletion of S4 analogues. The results showed that: (1) S4 is more active than S3 against RABV infection, 89% versus 38% inhibition at 7.5 μM; (2) the 5 NH2-aa of S4 are crucial for its inhibitory potential (S4 lost any inhibition) but the COOH terminus stabilizes the inhibitory potential (S4 showed only 23% inhibition at 7.5 μM); (3) there is a correlation between viral inhibition and dermaseptin cytotoxicity, which remains however moderated for BSR cells (≤12% at 10 μM). A single mutation in position 4 (S4) slightly reduced cytotoxicity while keeping its antiviral activity, 97% at 7.5 μM. S4 and S4 showed an antiviral activity in vitro when provided 1 h after infection. In vivo experiments in mice by intramuscular injection of non-toxic doses of dermaseptin S4 1 h post-infection by a lethal dose of RABV at the same site allowed more than 50% improvement in mice survival. This study highlights the potential interest of dermaseptins as non-expansive alternatives to rabies immunoglobulins for the treatment of rabies that continues to claim about 60,000 human lives per year worldwide, almost exclusively in developing countries.

Antimicrobial Peptides as Anticancer Agents: Functional Properties and Biological Activities

“…Moreover, DRS-S4 and DRS-S9 were shown to inhibit HIV-1 attachment to endometrial cells, the uptake by dendritic cells and subsequent viral spread to T-cells. DRS-S4 has shown to be effective against Rabies virus in mice [ 106 , 134 ].…”

Antiviral Ranpirnase TMR-001 Inhibits Rabies Virus Release and Cell-to-Cell Infection In Vitro

“…Recently, in vivo imaging was used to show favipiravir suppressed RABV replication in the periphery, but double or triple the dose was required to suppress replication in the CNS [40]. Another recent study also showed in vitro efficacy but limited effect in vivo of antimicrobial peptides dermaseptins against RABV in a mouse model [41]. These studies demonstrate that the in vivo delivery of rabies antivirals in animal models is a confounding factor that must be addressed in future rabies antiviral studies.…”

Antiviral peptides as promising therapeutic drugs

“…Thus, the authors suggested that there was a specific exchange of a Met4 by a Lys4 in dermaseptin S4, therefore, creating S4 M4K and decreasing cytotoxicity because of the substitution of a hydrophobic with a positively net charged amino acid. Given these results, not only do these dermaseptins have a virucidal mechanism of action, but they also affect early stages of the intracellular infection of the rabies virus [93].…”