Antiviral Peptides

Wouldn’t it be great if foods or drinks enabled us humans to prevent viral or bacterial infections? Or, if nasal or oral spray containing antiviral compounds prevented the infection of us humans by viruses. Imagine that there would be no flu, no colds, no AIDS or any other disease caused by a virus anymore and that the occurrence of these diseases is prevented by just eating or drinking one of your favorite foods or drinks. Surprisingly, some major food products, such as milk and milk based products, reported to be heavily consumed in some western, North African and other countries have been found to contain antiviral substances. When investigate some active components turned out to be proteins and peptides derived from the proteins present in the milk of mammals and humans. Especially some proteins and peptides found in adult milk or colostrum, the mother’s milk produced within the first 24 hours after birth, have been reported to bind to both virus particles and cellular receptors to prevent viral adsorption and entry, or to interfere with intracellular replication events or the synthesis of secondary viral components. Apparently milk, cheeses and yoghurt are foods that can help preventing viral and bacterial infections. Milk and cheese, both have been shown to contain proteins and peptides that have antiviral and antibacterial properties. And over the years many peptides have been found to prevent virus attacks or the entry of a virus into human cells. These types of peptides are called antiviral peptides.

H1N1 Flu Virus

Antiviral peptides (AVP) are peptides that have been experimentally verified to block virus attachment or the entry of a virus into host cells. It may just be possible that these types of peptides interfere with key steps a pathogenic mammalian and human virus needs to enter a cell. Scientists now hope that these inhibitory peptides could be used in the future as a starting point for the design of more active molecules for targeting of crucial molecules a virus needs to infect a host. The potential targets maybe carbohydrates, lipids, proteins, glycoproteins and oligonucleotides, involved in virus attachment, fusion and replication, and possibly other molecular functions yet to be determined. If this approach turns out to be successful antiviral peptides may become the preferred choice for the production of vaccines or therapeutics in the near future because of their relatively low molecular weight, lower toxicity, their rapid elimination from the host, possibly lesser side effects and also due to a lower cost if cost effective and efficient synthesis strategies are used.
 

A list of 144 antiviral peptides can be found in the “Antimicrobial Peptide Database (APD2)” [http://aps.unmc.edu/AP/main.php]. Peptides such as lactoferricin B, defensines, magainines, mellitins that have been experimentally verified to exhibit both antiviral and antibacterial activities and many others can be found in this database. Apparently, many of these peptides exhibit diverse activities including inhibition activities against gram positive and gram negative bacteria, viruses, fungi, some parasites, HIV, and even some mammalian cells or cancer cells. Many of these peptides originate from insects, frogs and mammals but may not be limited to just these species. For example, the casein proteins, whey proteins and their derived peptides found in milk all have antiviral activities and function as antiviral and immune regulatory factors by regulating the innate immune response. It has been found that the regulation is achieved by, both, up-regulation of the response to enhance the killing of viruses, and down-regulation to reduce detrimental conditions that may damage the host, for example, through sepsis, a potentially fatal whole-body inflammation caused by a severe infection.
 

In addition, VanCompernolle and others reported in 2005 that amphibian skin is a rich source of broad-spectrum antimicrobial peptides including some that haveantiviral activity. The research group identified three peptides called caerin 1.1, caerin 1.9, and maculatin 1.1 that completely inhibited HIV infection of T cells within minutes of exposure to the virus at concentrations that were not toxic to target cells. The researchers were also able to show that these peptides also suppressed infection by the murine leukemia virus but not by the reovirus, a structurally unrelated nonenveloped virus, and that preincubation using these peptides prevented viral fusion to target cells and disrupted the HIV envelope. The researchers could show that these amphibian peptides also were highly effective in inhibiting the transfer of HIV by dendritic cells to T cells. The scientists than reasoned that amphibian-derived peptides can access DC-sequestered HIV and destroy the virus before it can be transferred to T cells making these peptides promising tools that could function as topical inhibitors of mucosal HIV transmission.
 

Thakur et al. in 2012 reported in the Journal of Nucleic Acids Research a collection of 1245 peptides which were experimentally verified to have antiviral activity. The scientists reported that these peptides target important human viruses such as the influenza viruses, a RNA virus that causes the flu, the human immunodeficiency virus (HIV), a lentivirus that causes the acquired immunodeficiency syndrome (AIDS), ultimately resulting in the progressive failure of the immune system which than allows life-threatening opportunistic infections and cancers to develop in patients, the hepatitis C virus (HCV), a small, enveloped, positive-sense single-stranded RNA virus, that causes hepatitis C in humans, and the virus that causes the severe acute respiratory syndrome, a viral respiratory disease of zoonotic origin caused by the SARS coronavirus (SARS-CoV) (SARS), and multitude of other viruses. The research group reported that, after removing redundant peptides, they selected 1056 peptides which they further divided into 951 training and 105 validation data sets. Using features such as various peptides sequences, i.e. motifs and alignments followed by amino acid composition and physicochemical properties of the known antiviral peptides a bioinformatic approach called a “Support Vector Machine” approach was developed by this research group allowing the development and design of a prediction method algorithm for the identification of new antiviral peptides based on their amino acid sequences. The newly developed algorithm called AVPpred is a web server that allows the prediction of highly effective antiviral peptides that maybe helpful to researchers working on peptide-based antiviral development. The web server is freely available at http://crdd.osdd.net/servers/avppred.
 

The design of peptide based viral inhibitors is an example of the potential use of synthetic peptides to prevent viral infections. Miller at al. in 1989 described the early design of such a peptide inhibitor that was used to study its inhibitory effect on HIV-1 protease. The research group reported the structure of synthetic HIV-1 protease in complex with a substrate-based peptide inhibitor at a resolution of 2.3 Å. The hexa-peptide inhibitor containing the amino acid sequence N-acetyl-Thr-Ile-Nle-Ψ[CH2-NH]–Nle-Gln-Arg-amide was shown to bind to the active site of the protease in an extended conformation. The reasoning behind structural based studies is that the understanding of the details of inhibitor-enzyme or inhibitor-viral protein interactions will be useful for the design of potential efficient and effective antiviral or antibacterial peptides.

Miller M, Schneider J, Sathyanarayana BK, Toth MV, Marshall GR, Clawson L, Selk L, Kent SB, Wlodawer A.; Structure of Complex of Synthetic HIV-1 Protease with a Substrate-Based Inhibitor at 2.3 A Resolution. Science (1989) 246 p.1149
 

Nishant Thakur, Abid Qureshi, and Manoj Kumar; AVPpred: collection and prediction of highly effective antiviral peptides. Nucleic Acids Res. 2012 July; 40 (Web Server issue): W199–W204. Published online 2012 May 24. doi:  10.1093/nar/gks450, PMCID: PMC3394244.
 

Scott E. VanCompernolle, R. Jeffery Taylor, Kyra Oswald-Richter, Jiyang Jiang, Bryan E. Youree, John H. Bowie, Michael J. Tyler,  J. Michael Conlon, David Wade, Christopher Aiken, Terence S. Dermody, Vineet N. KewalRamani, Louise A. Rollins-Smith, and Derya Unutmaz;  Antimicrobial Peptides from Amphibian Skin Potently Inhibit Human Immunodeficiency Virus Infection and Transfer of Virus from Dendritic Cells to T Cells.  J. Virol. September 2005 vol. 79 no. 18 11598-11606.