Antiviral Human Antimicrobial Peptides

Posted on April 20th, 2020

Maxwell’s Peptoid drug class is designed to mimic an antimicrobial peptide used in the innate human immune system known as human cathelicidin antimicrobial peptide (hCAMP-18), hCAP18, or more simply LL-37. Although there are multiple cathelicidins found in nature, humans only express this single cathelicidin: LL-37. The biomimicry of Maxwell’s drug class includes LL-37’s functional hylical structure, the molecule’s folding properties, the amphipathic (use of both positive and negative charges) properties, and many of the mechanisms of action. This is a review of the published scientific studies showing the multiple mechanisms of action exhibited by natural immune peptides.

Natural immune peptides are amazingly broad-acting against every studied pathogen. However, they do not make optimal therapeutic drugs because they degrade too quickly inside the body (6 minutes). Maxwell’s peptoid drugs mimic the anti-infective qualities of natural peptides, while resisting degradation, allowing the Maxwell peptoids to continue to act on pathogens for at least 24 hours. [In Vivo Biodistribution and Small Animal PET of 64Cu Labeled Antimicrobial Peptoids, 2012]

Representative decay-corrected coronal small-animal positron emission tomography (PET) scan – an imaging test that helps reveal how tissues and organs are functioning and how a drug moves through the body. A PET scan uses a radioactive drug (tracer) to show this activity. These PET images of Balb/c mice are taken at different time points after administration with a Maxwell peptoid that has been tagged with a mildly radioactive form of copper (64Cu-1). The isotope-tagged molecule was administered through interperitoneal injection (A “IP”), oral chow (B “OP”), and intravenous injection (C “IV”) (n=4 for each group).

Multiple Mechanisms of Action

Maxwell’s scientists have studied peptoid mechanisms of action using electron microscopy photographs of membrane disruption. Our studies show that Maxwell’s peptoids attach to membranes with very similar mechanisms to LL-37. That said, identical properties cannot be assumed. We can use these LL-37 studies as a guide post for further study of peptoid mechanism of action.

LL-37 attaches to the membranes of pathogens, opens holes in the membranes, and then acts on the internal contents to bind the DNA and RNA, irreversibly inactivating the functional portions of the pathogen. Below is an image from a study published in Nature (2005) which shows LL-37’s mechanism of action against a membrane (illustrations A, B, C) and against nucleic acids, proteins and other internal structures (illustration  D).
antimicrobial peptide mechanism of action

Reproduced with permission. Copyright 2005, Nature.
Illustrated above are multiple mechanisms of action in which natural immune peptides attach to and disrupt the negatively charged outer membrane of a pathogen (A-C), and how natural peptides attack the inner workings of a pathogen (D). These mechanisms of action have been evidenced extensively in peer-reviewed publications, for Maxwell’s drug as well as the LL-37 peptide using multiple forms of imaging.

Assessing the interaction of antimicrobial peptides with phospholipids in model membranes provides some insight into their mechanisms of activity. The attraction, attachment, insertion and orientation of the peptide in the lipid bilayer can be determined by X-ray crystallography, NMR spectroscopy in solution and in the presence of lipid bilayers, and FTIR, Raman, fluorescence and CD optical spectroscopies. 
[Brogden, K. Antimicrobial peptides: pore formers or metabolic inhibitors in bacteria?. Nat Rev Microbiol 3, 238–250 (2005).]

Dr Annelise Barron et al present data in Nature, Scientific Reports (2017) demonstrating that peptoids (like natural immune peptides) are “fast killers”, which rapidly act inside the external membrane to attack and bind inner structures in vitro and in vivo such as proteins, DNA and RNA. Barron et al. suggest intracellular biomass flocculation as a key mechanism of killing. This process has a similar outcome to injecting glue into the gears of a complex machine. This novel flocculation mechanism of action may explain why peptoids require low concentrations (micromolar) for activity, show significant selectivity for killing negatively charged pathogens over mammalian cells, and finally, why development of resistance to Maxwell’s peptoids is less prevalent than developed resistance to conventional drugs.
[Chongsiriwatana, N.P., Lin, J.S., Kapoor, R. et al. Intracellular biomass flocculation as a key mechanism of rapid bacterial killing by cationic, amphipathic antimicrobial peptides and peptoidsSci Rep 7, 16718 (2017).]

Introduction to Antiviral Activity of Human Cathelicidin (LL-37)

Cathelicidins are a fundamental component of the innate immune system and play a vital role in the initial immune response generated against both injury and infections. Cathelicidin immune response is rapidly activated at the first stage of immune defense against infections. LL-37 is primarily synthesized and stored in cells of myeloid origin and epithelial cells, among the first responders to infections. LL-37 is expressed in a wide variety of tissues including skin, eyes, oral cavity, ears, airway, lung, female reproductive tract, cervical-vaginal fluid, intestines, and urinary tract [1,2].
Ahmed et al. in Human Antimicrobial Peptides as Therapeutics for Viral Infections, a review of relevant literature published in Viruses, 2019.


LL-37 has been studied for its activity against the viruses listed below, primarily observed in the peptide’s direct interaction with the outer envelope membrane. New studies are reporting that LL-37 binds proteins contained within the envelope, and several have observed LL-37 irreversibly binding RNA and DNA.

Influenza A Virus (IAV)

As shown in the illustration, Influenza is a negatively charged nano particle. Contained within the outer envelope is a capsid, which contains the RNA virus which the virus uses to replace human RNA and replicate itself inside of a human cell.

LL-37 therapeutic activity against influenza type A virus has been demonstrated in vivo and in vitro. It is likely that in vivo, IAV encounters LL-37 in the respiratory tract following innate immune responses against the virus and is secreted from neutrophils, macrophages, and epithelial cells [44 ,49 ].Early studies assessed the antiviral activity of LL-37 in vivo using a mouse IAV strain [50 ]. Mice were nebulized with LL-37 (500 g/ mL) a day prior to infection with a lethal dose of IVA PR/ 8 mouse strain, and survival and weight loss were monitored for 14 days following infection [50 ]. Initially, all mice exhibited weight loss, but weight loss ceased at day seven in mice treated with LL-37 or the IAV antiviral zanamivir. Mice treated with LL-37 and zanamivir exhibited 60% survival compared to the untreated group which succumbed to infection by day 9. This suggests that therapeutic use of LL-37 reduces IAV infection severity in a manner comparable to zanamivir [50 ]. LL-37 also decreased expression of inflammatory cytokines, particularly IL-1 , granulocyte-macrophage colony-stimulating factor (GM-CSF), keratinocytes chemoattractant (KC), and the chemotactic cytokine known as regulated on activation normal t-cell expressed and secreted (RANTES), in bronchoalveolar lavage fluid in mice infected with PR/ 8 two days following LL-37 treatment as determined by immunoassay demonstrating the immunomodulatory properties of LL-37 [50]. In vitro plaque assays demonstrated one log inhibition of PR/ 8 when virus was pre-incubated with LL-37 (50 g/ mL) in Madin-Darby canine kidney (MDCK) cells [50].
[Ahmed et al, 2019]

Human Immunodeficiency Virus (HIV)

Earlier studies provided evidence of LL-37’s ability to protect against HIV-1 infection given epithelial expression of LL-37, including in peripheral blood mononuclear cells such as CD4+  T-cells in vitro [52 ]. LL-37 directly inhibits the activity of HIV-1 reverse transcriptase via a protein–protein interaction in a dose-dependent manner (IC50 =  15 M) [9 ,53 ]. Inhibition of HIV-1 protease activity with LL-37 has also been reported; however, this activity is less potent when compared to inhibition of HIV-1 reverse transcriptase (20%–30% inhibition at 100 M). In addition, the plasma levels of LL-37 in HIV positive individuals undergoing antiretroviral therapy (ART) are much higher than in patients who are not, corresponding with an increased susceptibility to secondary infections in patients not undergoing ART [54].
[Ahmed et al, 2019]

Dengue Virus (DENV)

Treatment of dengue virus 2 (DENV-2) with LL-37 inhibits viral infection in green monkey kidney (Vero) cells. Incubation of virus with LL-37 (10-15 M) prior to infection inhibits production of viral particles, whereas pre-treatment of cells with LL-37 demonstrates no effect on viral replication [43 ]. Molecular docking studies of DENV-2 E protein have revealed the direct binding of LL-37 with E2 protein moieties, further demonstrating the peptide’s ability to act as an entry inhibitor [43 ].
[Ahmed et al, 2019]

Respiratory Syncytial Virus (RSV)

Respiratory syncytial (sin-SISH-uhl) virus, or RSV, is a common respiratory virus that usually causes mild, cold-like symptoms. Most people recover in a week or two, but RSV can be serious, especially for infants and older adults. In fact, RSV is the most common cause of bronchiolitis (inflammation of the small airways in the lung) and pneumonia (infection of the lungs) in children younger than 1 year of age in the United States. It is also a significant cause of respiratory illness in older adults. [Centers for Disease Control website, 30 March 2020)

A few studies have demonstrated the efficacy of LL-37 against RSV [11 ,57 ]. Cells pre-incubated with LL-37 (> 10 g/ mL) are protected against RSV infection whereas addition of LL-37 two hours post-infection results in decreased antiviral activity [57 ]. Additionally, LL-37 can limit viral-induced cell death in infected cell cultures, indicating that the peptide’s activity is not limited to prophylactic treatment. Treatment of epithelial cells with LL-37 prior to infection results in peptide internalization and retention, which provides antiviral protection for several hours post-treatment [57 ]. Furthermore, RSV infection induces the production of cytokines and chemokines in lungs. LL-37 (50 g/ mL) can impact the expression of chemokines as well as viral load when pre-incubated with RSV [11 ]. While the exact mechanism of the antiviral activity of LL-37 against RSV is not well established, it is speculated that the peptide directly interacts with the virus prior to infection, due to its dose-dependent early effects on RSV infection. Interestingly, children with lower cathelicidin levels are more susceptible to RSV infection and display an increase in the severity of RSV-associated bronchitis [58 ].
[Ahmed et al, 2019]

Human Rhinovirus (HRV)

Human rhinoviruses (HRVs) are causative agents of the common cold and most viral respiratory tract infections. As respiratory epithelial cells are the primary targets of HRV infection, studies evaluating the efficacy of LL-37 on HRV have utilized airway epithelial cells. LL-37 (50 g/ mL) demonstrates direct antiviral activity against HRV when added as a pre-treatment by acting on viral particles, and when added post-infection by acting on the host cell [59 ]. LL-37 can induce a significant reduction in the metabolic activity of infected cells, as measured by mitochondrial metabolic potential [59 ]. Studies evaluating HRV in cystic fibrosis cells have revealed that expression of LL-37 decreases HRV viral load in vivo [60 ]. Thus, LL-37 reduces HRV infections in respiratory cells as well as in cystic fibrosis cells.
[Ahmed et al, 2019]

Vaccinia Virus (VACV)

Vaccinia virus (VACV) is a DNA virus that can infect many types of mammalian cells. LL-37 limits VACV replication and can alter viral membranes [61 ]. VACV gene expression and viral titers are reduced in a dose-dependent manner in cells pre-incubated with LL-37 (25–50 M) [61 ]. Transmission electron microscopy images have shown a disruption in the integrity of VACV viral membrane after 24 hour incubation with LL-37. Whereas murine LL-37 has demonstrated great efficacy and protection against VACV during infection, the efficacy of human LL-37 against VACV is unknown [61 ].
[Ahmed et al, 2019]

Herpes Simplex Virus (HSV)

Maxwell scientists have studied our peptoid drug candidates against HSV-1 in human mouth epithelial cells and human lung cells. Each cell line showed similar results to the LL-37 studies in human corneal cell line discussed in Ahmed et al, 2019.

LL-37 (500 g/ mL) can inhibit HSV-1 infection when pre-incubated with virions in vitro (human corneal cell line) [62 ]. LL-37 reduces viral titers in corneal epithelial cells by more than 100-fold when compared to a scrambled LL-37 control [62 ]. Another study evaluating the anti-HSV-1 activity on corneal implants assessed the release of LL-37 delivered through corneal implant-incorporated nanoparticles [63 ]. Whereas LL-37 did not clear viruses from infected cells, it blocked HSV-1 infection in corneal epithelial cells by preventing viral-cell attachment [63 ]. These studies reinforce the mechanism of LL-37 antiviral activity as entry inhibition.
[Ahmed et al, 2019]

Zika Virus (ZIKV)

Zika virus (ZIKV) is a positive-sense, single-stranded RNA virus that can cause fever, headaches, rashes, joint pain, and myalgia in children and adults, and “microcephaly, ventriculomegaly, intracranial calcifications, abnormalities of the corpus callosum, retinal lesions, craniofacial disorder, hearing loss, and dysphagia” in neonates [65 ]. The emergence of ZIKV is a global concern since it is the first major infectious disease that has been associated with birth defects in over five decades [66 ]. Currently, no vaccines or treatments are available to prevent ZIKV infection [66 ]. He et al. [46 ] conducted a study to determine whether LL-37 and synthetic derivatives can be used to treat ZIKV infection in primary human fetal astrocytes [46 ]. Whereas LL-37 is toxic to these cells (EC50 =  20 M), an LL-37 derivative, GF-17, can be safely used due to its lower toxicity (EC50 >  50 M) [46 ]. Treatment of primary human fetal astrocytes with 10 M of GF-17 24 h after ZIKV infection results in a seven-fold decrease in the number of ZIKV plaque forming units [46 ]. Pre-incubation of ZIKV between 1 and 4 h with GF-17 (10 M), results in at least a 95% decrease in the number of active zika virions [46 ]. In addition to the possibility of GF-17 directly interacting with ZIKV virions as a mechanism of antiviral activity, GF-17 increases interferon- 2 (IFN- 2) expression in a dose-dependent manner, which further impacts the ability of ZIKV to infect primary human fetal astrocytes [46 ].
[Ahmed et al, 2019]

Hepatitis C Virus (HCV)

Maxwell’s peptoids have been tested against HCV. Data from the Institute of Infectious Diseases, Tokyo (Japan’s CDC) shows that multiple Peptoid drug candidates are rapidly and remarkably effective against Hepatitis C, which is an RNA virus. It is remarkable because our drugs are also effective against Herpes Simplex Virus 1 which is a DNA virus.

Venezuelan Equine Encephalitis Virus (VEEV)

Scientists at the National Center for Biodefense and Infectious Disease at George Mason University, tested the host defense peptide LL-37 against VEEV. Their data shows that LL-37 “exhibits robust antiviral activity with minimal toxicity” to humans. Their works appears to show that treatment of the virus with LL-37 appears to block the virus from entering human cells. Additionally, they found that LL-37 enhanced type I interferon (IFN) expression in infected host cells, creating an antiviral state inside the infected cell. LL-37 also inhibited the most virulent strain of VEEV – the Trinidad Donkey (TrD) strain.

Venezuelan equine encephalitis virus (VEEV), a new world alphavirus belonging to the Togaviridae family, causes periodic disease outbreaks in humans and equines with high associated mortality and morbidity. VEEV is highly infectious via the aerosol route and so has been developed as a biological weapon (Hawley and Eitzen, 2001). Despite its current classification as a category B select agent, there are no FDA approved vaccines or therapeutics to counter VEEV infections. [Human cathelicidin peptide LL-37 as a therapeutic antiviral targeting Venezuelan equine encephalitis virus infections, Antiviral Research, April 2019]

Mechanisms of Action

1) Generally, irreversible action on the viral architecture to inhibit entry into human cells

Almost universally, pre-incubation of free virus particles prior to attempted infection of human cells appears to be the most successful strategy for LL-37’s ability to inhibit viral replication. If the virus cannot enter the host cell, then the virus is not able to replicate and is irreversibly inactivated. This has multiple benefits in that it acts rapidly, prevents further cellular damage, and acts on the core cause of host disease pathology, and most importantly eliminates the that inactivated virus permanently.

Entry assays revealed a robust reduction of viral RNA copies at the early stages of TC-83 infection. Pre-incubation of cells with LL-37 resulted in a strong inhibitory response, indicating that LL-37 impacts early stages of the infectious process. [Human cathelicidin peptide LL-37 as a therapeutic antiviral targeting Venezuelan equine encephalitis virus infections, Antiviral Research, April 2019]

2) Carpet Model of Viral Envelope Removal

LL-37 is proposed to remove the outer membrane of viruses in a single event rather than gradual piece-by-piece removal. [37] This suggests a carpet model of antimicrobial peptide action, wherein a susceptible membrane remains intact until a threshold concentration of peptide is reached, following which a rapid disintegration of the targeted membrane occurs. [47,48]. [Ahmed et al, 2019]

Density gradient analysis of the treated virions indicated the virus outer membrane was efficiently removed by peptide action and suggests a mechanism of direct virus inactivation that is consistent with the carpet model for peptide-mediated membrane disruption. [47] [Dean, R. E., et al, 2010]

3) Exposure of viral antigens sequestered beneath the outer viral membrane envelope

Removing the outer membrane – removing the viruses mask – exposes the virus to the adaptive immune system, and allows the body to tag the virus with antibodies for removal.

Interestingly, the least effective peptide uperin-3.1 was equally effective as the others at inducing susceptibility to neutralizing antibody. This suggests that in addition to direct killing by a carpet-based mechanism, the peptides may simultaneously operate a different mechanism that exposes sequestered antigen without membrane removal. [47] [Dean, R. E., et al, 2010]

4) Inactivation by Flocculation or Aggregation of Negatively Charged Viral Particles

Maxwell’s drug is similar to LL-37 in that they  both use an electrostatic mechanism of action: positively charged nanoparticles are attracted to negatively charged nanoparticles. Viral membranes, RNA, and DNA are negatively charged, and therefore are irresistibly attractive to positively charged aspects of LL-37 and Maxwell’s peptoid drugs. Once associated with the membrane of the pathogen, the positively charged elements of the natural peptides and the synthetic peptoids tend to attract other viruses causing the viruses to stick to each other as if glued together – causing immobilization and inactivation via biomass clumping, flocculation or aggregation.

Confocal and electron microscopy images confirmed the aggregation of viral particles, which potentially accounts for entry prevention and hence reduced viral infection. [Human cathelicidin peptide LL-37 as a therapeutic antiviral targeting Venezuelan equine encephalitis virus infections, Antiviral Research, April 2019]

Stanford University’s Dr. Annelise Barron published data in Nature Scientific Reports [Intracellular Biomass Flocculation as a Key Mechanism of Rapid Bacterial Killing by Cationic, Amphipathic Antimicrobial Peptides and Peptoids, 2017] that showed the same mechanism of action occurs in bacteria treated with LL-37 and with Maxwell’s peptoid drugs. This may be applicable to peptoid activity against viruses because the electrostatic elements are very similar, and the bacterial aggregation occurred in internal organelles and structures such as DNA and RNA which are shared with viral structures. In photo A of the image below, it is apparent that the internal distribution of an untreated bacteria shows a relatively uniform distribution of internal systems. In photos E, F, G, H and I, aggregation of RNA, DNA and other internal systems is illustrated using transmission electron microscope imaging.


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