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Research News at Memorial Hospital
   Andrew Artenstein, MD

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   Steven Opal, MD

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Two of Memorial Hospital of Rhode Island's doctors, Andrew Artenstein, MD, Physician-in-chief of medicine and Steven Opal, MD, Chief of Infectious Disease, have an important research study in the December 29th, 2011 edition of The New England Journal of Medicine regarding Proprotein Convertases in Health and Disease.

A summary of the article:

Many of the body’s most important proteins, including hormones, receptors, and growth factors, are produced as inactive precursor proteins and must be activated in order to be functional.  Such activation requires specific enzymes.  These enzymes--proprotein convertases (PCs)—represent a family of nine different proteins (enzymes) that were discovered approximately two decades ago.  A large amount of information about their role in human health has been accumulating since that time.  More recently, they have been shown to play a role in a wide variety of different types of human disease process, such as cancer, hormonal disorders, infectious diseases, cholesterol disorders, and Alzheimer’s disease.  Because PCs play a role in the development of disease, they may also be potential targets for new approaches to treatment.  As scientists gain more insights into the role that PCs play in the development of various diseases, they also identify new opportunities to treat these disorders, and this could lead to breakthroughs in the treatment of various cancers and serious infections that could help a large number of patients.


Proprotein Convertases in Health and Disease

Andrew Artenstein, M.D. and Steven M. Opal, M.D.
December 29, 2011


Questions and Answers with Andrew Artenstein, M.D.
What good do proprotein convertases do for the body?
Proteins are the building blocks of nearly all important parts of cells, tissues, and organs in the human body. Enzymes are specific types of proteins that trigger important chemical reactions in the body and are necessary for human life. Proprotein convertases (PCs) are a unique family of enzymes that turn a wide range of non-functional human proteins into active, functional proteins.  Without them, our bodies would not be able to sustain life.  Evidence for this comes mostly from studies in mice which show that deficiencies of certain members of the PC family result in severe and often fatal outcomes. Three natural cases of human deficiencies have been associated with profound hormonal disorders.

Why are they implicated in such an astonishingly wide variety of diseases?
PCs have been shown to be involved in a wide variety of disease processes.  Most of this information comes from studies in animals, although some comes from humans.  They may play a role in the development of various types cancer, atherosclerosis, Alzheimer’s disease, hormonal disorders, and various important infections, like influenza, anthrax, and numerous other viral and bacterial toxin diseases.  The reason for their involvement in infectious diseases is that various toxins produced by bacteria such as anthrax and diphtheria need to be activated before they can become dangerous—they use PCs to become functional.  A number of different viruses, such as influenza, Ebola, and measles, hijack PCs from the humans they infect in order to help themselves complete their life cycle and reproduce in the body.  In Alzheimer’s diseases, PCs are necessary for the formation of the “senile plaques”—the brain abnormalities seen in this disorder.  All of this stems from the crucial role that PCs play in activating proteins in humans.

Have scientists had much luck in developing ways to fix problems (such as through inhibition) associated with the enzymes?

Just over the past decade, a lot of research has been underway to study the effects of blocking the action of various PCs to see if various disease processes could be prevented.  Some promising results, from a number of different labs around the world, have shown that blocking PC activity may prevent cells from becoming cancerous and may also prevent the development of various tumors in mice.  Studies have also shown that by blocking PCs, scientists can prevent a tumor from spreading in the body.  At the Center for Biodefense and Emerging Pathogens at Memorial Hospital of Rhode Island and the Warren Alpert Medical School of Brown University, we have been studying the effects of blocking PCs through novel treatment strategies on anthrax infection and on influenza virus infection.  These studies in mice and cell lines, have shown promising early results and suggest that severe disease and death may be prevented by inhibiting different PC functions.

Although the enzymes are associated with many diseases (natural or induced by potential bioterror attacks), they are only one player in a sequence of events. Why do you think that targeting them could have meaningful therapeutic effects?
Many diseases have more than one specific cause or trigger that results in sickness or death.  For example, the process of cancer, involves multiple steps at the microscopic level, and each step is associated with numerous different pathways that involves a large variety of different molecules that perform different functions.  Although the development and progression of cancers and various types of infectious diseases is complex, and PCs are only one part of these processes, they do seem to play a crucial and necessary part that allows the process to continue.  Therefore, blocking their action may represent one approach to treating these disorders.  Of course, other approaches may need to be part of the strategy as well.

What are the most promising strategies for developing therapies based targeting proprotein convertases?
At the Center for Biodefense and Emerging Pathogens and the Department of Medicine at Memorial, we have special interest and expertise in the area of biodefense.  Biodefense involves ways to prevent and treat infections resulting from bioterrorism and also infections that arise through nature; these are much more common than bioterrorism and occur almost every year.  Good recent examples include the outbreak of H1N1 swine influenza in 2009, cholera in Haiti, severe anthrax among drug users in Europe in 2010, and SARS, among others.  We are interested in developing a therapeutic agent that could be used against a wide variety of different possible infections because frequently scientists cannot easily and rapidly identify the actual culprit in a rapidly spreading epidemic or a bioterror attack—therefore it would be helpful to have a drug that treats a variety of problems. Because PCs are a common denominator in a large number of infections, we have targeted PCs as a therapeutic strategy in our research.  We have identified a group of natural human proteins, called inter-alpha-inhibitor proteins (IaIps) that block the activity of PCs and have shown promise in animal models of anthrax and in cells infected with influenza.  We are now expanding our studies to include a large number of other bacteria and viruses. 

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