http://en.wikipedia.org/wiki/Melittin

Artist and scientist Julian Voss-Andreae has created a sculpture based on the structure of melittin, which he mentions in a talk about his work. (http://en.wikipedia.org/wiki/Melittin)

by Roseann Vorce, Ph.D., 
Department of Pharmacology and Toxicology, Michigan State University 

In addition to last week’s news about a functional cure of HIV in an infant, a paper describing the ability of bee venom to destroy HIV was published in the journal “Antiviral Therapy”.  Anyone who has been stung by a bee is probably cringing at the prospect of receiving bee venom, because bee stings hurt!  Much of the pain you experience from a bee sting is caused by melittin, the primary active component in bee venom.  HIV researchers have taken the sting out of melittin therapy by cleverly packaging this toxin in a form that prevents it from reaching your cells.  This breakthrough finding represents a change in the form of melittin, not in its function.  By manipulating the form of melittin, it has been converted from a general toxin to a virus-specific drug.  The concept of controlling the function of a compound by changing its physical form represents a novel way to develop new drugs from old compounds.

Before we get into the bioengineering aspects of this development in HIV prevention, let’s first discuss the mechanism by which melittin destroys HIV.  Melittin is a small protein consisting of 26 amino acids.  The hydrophilic carboxy-terminus accounts for its water soluble nature, whereas the hydrophobic amino terminus promotes its spontaneous and rapid interactions with phospholipid membranes.  These interactions damage membranes in a nonspecific manner, severely compromising membrane structure and function.  Some viruses, including HIV, are surrounded by a lipid membrane called the viral envelope, and such viruses require an intact viral envelope to infect cells.  If the lipid envelope of HIV is disrupted, HIV is rendered non-infective.  By virtue of its ability to damage membranes, melittin disrupts the viral envelope surrounding HIV, thereby destroying the ability of HIV to infect cells.  For this reason, scientists have studied melittin as a chemoprophylactic substance that can inhibit infection of HIV and disrupt the transmission of this virus.

Although melittin destroys the infectivity of HIV particles, the utility of this toxin is limited by its nonspecific cytotoxic effects:  melittin kills cells by disrupting membrane structure and function.  If administered directly to humans, melittin would kill any cell it encounters, causing widespread tissue damage.  Therefore, the researchers needed to develop a method to deliver melittin so that it comes into contact with HIV particles, but not human cells.  Although this problem appears to be nearly insurmountable, the recent developments in nanoparticle-mediated drug delivery provided the investigators with a tool to limit contact with melittin that is based on the large size difference between tiny viral particles and comparatively large human cells.

Nanoparticles are extremely small particles that can be engineered to exhibit precise physicochemical properties.  In recent years, scientists have harnessed nanoparticles to deliver drugs and other bioactive substances to solve challenging pharmacokinetic problems.  Nanoparticles used for drug delivery, which typically range in size from approximately 1 to 100 nanometers, can be composed of a variety of pharmacologically inert materials.  Drugs attached to the nanoparticles can gain access to any compartment available to the nanoparticle; through careful engineering, nanoparticles can be targeted to specific cell types, tissues, or organs.

https://i1.wp.com/news.wustl.edu/news/PublishingImages/HIVnano_primary.jpg

JOSHUA L. HOOD, MD, PhD – Nanoparticles (purple) carrying melittin (green) fuse with HIV (small circles with spiked outer ring), destroying the virus’s protective envelope. Molecular bumpers (small red ovals) prevent the nanoparticles from harming the body’s normal cells, which are much larger in size. (click on image to be directed to Washington University in St. Louis article.)

In the Antiviral Therapy paper, HIV researchers used nanoparticles to destroy the infectivity of HIV by allowing viral particles access to melittin, while excluding human cells.  First, they created nanoparticles composed of a perfluorocarbon (PFC) core and “molecular bumpers” made of polyethylene glycol (PEG).  Next, they attached melittin to the PFC core.  In the presence of human cells, the large PEG molecules on the outside of the nanoparticle physically prevent the large cells from reaching the core surface, effectively preventing interactions between the cell membranes and the melittin located on the nanoparticle core.   Because HIV viral particles are much smaller than the human cells, the virus readily slips between the bumpers and comes into contact with melittin.  Upon contact, the melittin disrupts the viral envelope, and the HIV loses the ability to infect the cells.  Using this strategy, researchers demonstrated that these melittin nanoparticles dramatically decrease HIV infectivity, without harming human cells. In other words, through careful engineering of melittin nanoparticles, scientists have blocked human cells from contact with melittin, while allowing this toxin to interact with and inactivate HIV.

Melittin nanoparticles represent an advance in HIV therapy because this approach carries the potential for future development as a prophylactic agent.  In contrast, traditional antiretroviral agents inhibit viral replication within human cells to decrease viral load, but they cannot stop HIV from infecting human cells.  By destroying HIV infectivity, melittin nanoparticles can prevent HIV infection.  Researchers envision development of a vaginal gel containing melittin nanoparticles that will prevent the transmission of HIV between partners who wish to become pregnant or in areas where cultural norms prevent condom use.  Of course, a vaginal gel does not provide protection for people engaging in alternative sexual practices or who risk contracting HIV through intravenous drug use.  However, because melittin is an agent that destroys an essential component of the HIV virus, this toxin also holds the potential to cure HIV.  Researchers have speculated that melittin nanoparticles might someday be administered as an intravenous injection, able to completely clear HIV from the body.  In the future, using a combination of traditional antiretroviral drugs, novel therapeutic agents and treatment regimens, and new approaches for drug delivery, perhaps HIV will become a curable disease.

References:
Hood JL, Jallouk AP, Campbell N, Ratner L, and Wickline SA.  Cytolytic nanoparticles attenuate HIV-1 infectivity.  Antiviral Therapy 18:95-103, 2013.

http://news.wustl.edu/news/Pages/25061.aspx

Faraji, AH and Wipf, P.  Nanoparticles in cellular drug delivery.  Bioorganic & Medicinal Chemistry 17:2950-2962, 2009.

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