Study of alloferon, a novel immunomodulatory antimicrobial peptide (AMP), and its analogues

Abstract

Antimicrobial peptides (AMPs) are widely distributed throughout the biosphere and represent a class of conserved peptide molecules with intrinsic antimicrobial properties. Their broad-spectrum antimicrobial activity and low risk to induce resistance have led to increased interest in AMPs as potential alternatives to traditional antibiotics. Among the AMPs, alloferon has been addressed due to its immunomodulatory properties that augment both innate and adaptive immune responses against various pathogens. Alloferon and its analogues have demonstrated pharmaceutical potential through their ability to enhance Natural Killer (NK) cell cytotoxicity and stimulate interferon (IFN) synthesis in both mouse and human models. Additionally, they have shown promise in augmenting antiviral and antitumor activities in mice. In this article, we provide a comprehensive review of the biological effects of alloferon and its analogues, incorporating our own research findings as well. These insights may contribute to a deeper understanding of the therapeutic potential of these novel AMPs.

Keywords: IFN; NK cell; alloferon; antimicrobial peptides; antivirus.

FIGURE 1

Primary structural formula of alloferon. The structural formula of alloferon with molecular formula: C₅₂H₇₆N₂₂O_16; H-His-Gly-Val-Ser-Gly-His-Gly-Gln-His-Gly-Val-His-Gly-OH.

FIGURE 2

Hypothetical model for the antiviral effect of alloferon via the NF-κB pathway. Alloferon may act as an activator or inhibitor of the NF-B pathway depending on the function of the pathway in the host. During viral infections, alloferon treatment may help activate receptors and signals that boost the NF-κB pathway through IKK phosphorylation. Activation of NF-κB by alloferon causes stimulation of the IFN-α which is responsible for boosting the innate immune system to fight against the cancer or virally infected cells. On the other hand, some viruses may alter the NF-κB pathway for their benefit to induce stress responses and prevent apoptosis of the infected cells. Alloferon treatment may then act as an inhibitor of the NF-κB pathway by preventing IKK activation and blocking expression of the viral gene because some viruses possess binding sites for transcription by NF-κB.

FIGURE 3

Anticancer and antiviral mechanisms of alloferon. NK cells provide early protection against cancerous and viral infected cells by producing cytokines and exerting direct cytolytic activity. Alloferon increases NK cells’ cytotoxicity following two main mechanisms: (1) Cytotoxicity via secretion of lytic/exocytotic granule. The lytic granules: perforin and granzymes functions after infected cell and NK cell interaction. Perforin causes the cell to become permeable whereas granzymes cause damage to DNA, stop the cell cycle, and destroy the nucleus when they enter the cell. (2) Increasing the production of IFN-γ and TNF-α via the NF-κB pathway. Through the generation of IFN-γ, activated NK cells generate effector activity that directly reduces host cell hospitability to the virus and can operate indirectly to prevent infection in other cells. Additionally, they recruit and activate additional effector leukocytes.