MAYLAND CHANG
Research Professor at University of Notre Dame
https://www.linkedin.com/in/mayland-chang-97b1b432
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MAYLAND CHANG
- Research Professor; Director, Chemistry-Biochemistry-Biology Interface (CBBI) Program
- Office: 247 NSH
- Phone: (574) 631-2965
Dr. Chang obtained B.S. degrees in
biological sciences and chemistry from the University of Southern
California, and a Ph.D. in chemistry from the University of Chicago.
Subsequently, she conducted postdoctoral research at Columbia University
as a National Institutes of Health postdoctoral fellow. She joined the
faculty of the University of Notre Dame in 2003. Previously, Dr. Chang
was Chief Operating Officer of University Research Network,
Inc., Senior Scientist with Pharmacia Corporation, and Senior Chemist at
Dow Chemical Company. She has characterized the ADME properties
of numerous drugs, as well as prepared NDAs, INDs, Investigator’s
Brochures, product development plans, and candidate drug evaluations.
The Chang lab conducts biomedical research to understand the molecular basis of disease and to design small molecules for therapeutic intervention. Some of our current projects are:
SB-3CT is a selective gelatinase (MMP-2 and MMP-9) inhibitor that shows efficacy in animal models of stroke, traumatic brain injury, and cancer metastasis. SB-3CT, however, is poorly water soluble and is extensively metabolized. We used a prodrug strategy to increase >5000-fold the aqueous solubility of SB-3CT. The prodrugs are hydrolyzed in human blood within 30 minutes, generating the active gelatinase inhibitors. One of the prodrugs (referred to as ND-478) has excellent pharmacokinetic properties. This class of compounds is rapidly absorbed andis readily distributed to the brain. Efficacy studies in animal models of stroke and traumatic brain injury are currently being conducted.
Chronic wounds are a complication of diabetes and are characterized by inflammation, altered MMP expression, and deregulation of apoptosis. We used an affinity resin that binds only the active forms of MMPs and related ADAMs coupled with quantitative proteomics to identify active MMPs in diabetic wounds. Using the selective MMP-9 inhibitor ND-322 led to acceleration of wound healing accompanied by re-epithelialization. This represents the first pharmacological intervention in treatment of diabetic wounds. Studies to confirm the roles of these MMPs in diabetic wound healing are underway.
Another project involves the design, syntheses, and evaluation of novel antibiotics to treat methicillin-resistant Staphylococcus aureus infections. We have identified two lead templates that show high in vitro activity and promising antibacterial activity in a mouse model of infection. Their pharmacokinetic properties are being optimized. Identification of the target is being pursued by photoaffinity labeling at the whole proteome level, as well as obtaining an X-ray crystal structure of the compounds with the putative target.
Research Professor, Chemistry & Biochemistry
University of Notre Dame
Email: Mayland Chang
Phone: 574-631-6533
Office: 163 Stepan Hall
Mayland Chang, Department of Chemistry and Biochemistry, is working on ways to inhibit cancer metastasis, the spreading of the out-of-control cells to other organs. Although metastasis is a leading reason that cancer becomes fatal, primary tumors rarely kill and often can be treated, no anti-metastatic agent has been commercialized to treat aggressive cancers. Meanwhile, metastasis of breast and prostate cancer, for example, leads to further life-threatening complications that cause tens of thousands of deaths each year.
Building on studies showing that the matrix metal-loproteinases are associated with cancer progression and metastasis in many types of cancers, a few years ago discovered and
synthesized the first prototype selective mechanism-based inhibitor found to be effective in mouse models of prostate cancer metastasis to the bone, breast cancer metastasis to the lungs, and T-cell lymphoma metastasis to the liver. This work has progressed in the direction of compounds that can be used in additional in vivo models for disease, leading to second and third-generation compounds. The researchers are now refining related compounds with the goal of developing selective inhibitors that can advance forward to preclinical development and ultimate entry into clinical trials for the treatment of cancer metastasis.
Mayland
Chang, PhD, is bringing scientific discoveries out of academia to the
masses, from new antibiotics to the treatment of skull-crunching head
injuries on the football field.
Chang, a faculty member in the Department of Chemistry and Biochemistry, was recently awarded a five year, $5.5 million dollar grant from the National Institute of Allergy and Infectious Diseases (NIAID). She is also the recent recipient of an NFL Charities grant to design and develop therapeutics for the treatment of traumatic brain injury (TBI).
The NIAID grant, a considerably large amount for research grants, will fund translational research aimed at the discovery and development of drugs to fight serious gram-positive bacterial infections such as methicillian resistant Staphylococcus aureus (MRSA). Translational research is described by Chang as “bench to bedside” research, which leads to practical applications in patients.
Chang obtained B.S. degrees in biological sciences and chemistry from the University of Southern California, and a Ph.D. in chemistry from the University of Chicago. She joined Notre Dame in 2003.
Chang recently spoke with ND Today about her research, teaching at Notre Dame, and her hobbies.
ND Today: What does it mean to you to receive the NIAID grant?
Mayland Chang: There is a dearth of research on new antibacterials, as the economic incentives are not there for pharmaceutical companies to pursue discovery and development of antibiotics. Because fewer pharmaceutical companies are focusing on antibacterials (most have abandoned the field), academic institutions have to step up to discover and develop new classes of antibiotics. This grant allows us to do just that.
ND Today: Tell us about your NFL Charities Grant – what type of research will you be doing?
MC: Traumatic brain injury (TBI) is one of the leading causes of death and disability in the industrialized world. A TBI is caused by a bump, blow, or jolt to the head or a penetrating head injury that disrupts the normal function of the brain. The majority of TBIs (75%) are concussions. Concussions are a prominent feature of sports, with 300,000 reported concussions in the U.S. occurring while playing sports. Concussions result from a blow to the head that produces a cascade of neurological events, resulting in reduced blood flow to the brain, brain cell injury, and death.
A contributing factor to these pathological processes is the activation of enzymes called matrix metalloproteinases (MMPs), particularly gelatinases (MMP-2 and MMP-9). There are presently no therapeutics for TBI. Research in the field lacks presently the ability to rescue brain cells after each concussion or any damage to the brain. If a medication could be given after such a damage that rescues the brain cells destined to die that would move the field forward in treatment of TBI significantly. The NFL Charities grant will support groundbreaking research that has the potential for the development of such a treatment for TBI. We have developed a prototype inhibitor, which potently decreases brain damage and hemorrhagic injury. We have synthesized water-soluble inhibitors, which are amenable to intravenous administration, the preferred route of administration for TBI. These results hold outstanding promise for important applications in fighting gelatinase-mediated consequences of brain damage after TBI in patients.NFL funding will open the door for expansion of this project in directions that we hope will lead to treatments for TBI.
ND Today: How did you come to specialize in chemistry?
MC: I grew up in Ecuador and was good in math and science. As a high school student, I only knew of professional careers, such as medicine. I came to the US for college and as an undergraduate at USC I started as a biology major. There was no pre-med major at USC. After taking analytical chemistry as a junior in college, I decided to pursue chemistry. I ended up with a BS in biology and a BS in chemistry. Then I went to graduate school at the University of Chicago and got my PhD as a natural products chemist and post-doc at Columbia University in bioanalytical chemistry. When I was looking for a job, I could not find a position in the industry in natural products chemistry. I ended up doing metabolism of herbicides and insecticides at Dow Chemical. From there I moved to Upjohn. Before moving to Notre Dame, I was COO of University Research Network, Inc., an academic research organization that I established for Wayne State University School of Medicine that facilitated clinical research and provided clinical development services to the pharmaceutical and biotechnology industries.
ND Today: What is the best part about working at Notre Dame?
MC: The opportunity to work with and train talented undergraduate students. Since I came to Notre Dame, I have had nine undergraduates in the lab—four have graduated, one is in grad school at Madison Wisconsin, one is in an MD PhD program at Washington University, one is in an MD program at Loyola, and one is in an MD program at Rochester.
ND Today: Given the very serious nature of your work, what do you like to do to unwind?
MC: Gourmet cooking. Cooking is very much like chemistry. I wanted to be a chef but it was not an acceptable profession [in her home country]. Gardening—pulling weeds relieves stress, and travel—traveling is part of one’s education—it opens the mind to new experiences and cultures. I love to spend time with my cats Misty and Carbon, and watching birds in my backyard. Rain or shine, I feed the birds year-round.
Mayland Chang
Diabetes affects more than 29 million Americans, or 9.3 percent of
the population. One of the many complications of the disease is the
inability of wounds to heal properly because diabetic patients often
have nerve damage, weakened immune systems or narrow arteries. In 2010,
73,000 non-traumatic lower-limb amputations were performed in the United
States due to diabetes.
The American Diabetes Association (ADA) announced Tuesday that it is funding a $1.6 million Accelerator Award to Mayland Chang, research professor of chemistry and biochemistry at the University of Notre Dame, to help lower that number. The research award, part of the association’s Pathway Awards program, will provide funding for Chang’s project, “A Strategy to Accelerate Diabetic Wound Repair,” over five years.
Chang’s research is broadly focused on exploring the molecular basis of disease and designing small molecules for therapeutic interventions. She has ongoing projects related to stroke, traumatic brain injury, cancer metastasis and MRSA (methicillin-resistant Staphylococcus aureus). A newer area of work for Chang is to understand why diabetic wounds are so difficult to treat and to develop novel therapeutics to promote wound healing.
Using a mouse model and a novel diagnostic resin that binds to active forms of matrix metalloproteinases (MMPs), proteases involved in tissue remodeling, Chang’s research group found that MMP-9 may cause diabetic wounds and MMP-8 may be involved in wound repair. They also demonstrated that selective pharmacological inhibition of MMP-8 delayed wound repair and inhibition of MMP-9 accelerated wound healing.
Using a combination of research techniques, Chang’s project will identify the mechanisms associated with diabetic wound development, progression and healing; study bacterial colonization in diabetic wounds; and find interventions that expedite the healing process. To achieve these goals, she will validate the roles of MMP-8 and MMP-9 in diabetic wounds, investigate the relevance of these MMPs in human patients, evaluate novel MMP-9 inhibitors and determine the contribution of bacterial infection on wound repair.
“This research project will allow intervention of chronic wounds, a complication of diabetes for which pharmacological clinical recourse is not available,” Chang said. “Our work holds great promise in addressing an unmet medical need.”
Accelerator Awards are designed to support early-career investigators or established researchers who are accomplished in other fields, but would like to apply their expertise to innovative diabetes-related research topics.
Contact: Mayland Chang, 574-631-2965, mchang@nd.edu
////
- Research Professor; Director, Chemistry-Biochemistry-Biology Interface (CBBI) Program
- Office: 247 NSH
- Phone: (574) 631-2965
- Send an email
Primary Research Areas
Research Specialties
Experience
Director, CBBI Program
University of Notre Dame
Research Professor
University of Notre Dame
Senior Scientist
Pharmacia
Senior Chemist
Dow Chemical
Education
University of Chicago
Ph.D., Chemistry
The Chang lab conducts biomedical research to understand the molecular basis of disease and to design small molecules for therapeutic intervention. Some of our current projects are:
SB-3CT is a selective gelatinase (MMP-2 and MMP-9) inhibitor that shows efficacy in animal models of stroke, traumatic brain injury, and cancer metastasis. SB-3CT, however, is poorly water soluble and is extensively metabolized. We used a prodrug strategy to increase >5000-fold the aqueous solubility of SB-3CT. The prodrugs are hydrolyzed in human blood within 30 minutes, generating the active gelatinase inhibitors. One of the prodrugs (referred to as ND-478) has excellent pharmacokinetic properties. This class of compounds is rapidly absorbed andis readily distributed to the brain. Efficacy studies in animal models of stroke and traumatic brain injury are currently being conducted.
Chronic wounds are a complication of diabetes and are characterized by inflammation, altered MMP expression, and deregulation of apoptosis. We used an affinity resin that binds only the active forms of MMPs and related ADAMs coupled with quantitative proteomics to identify active MMPs in diabetic wounds. Using the selective MMP-9 inhibitor ND-322 led to acceleration of wound healing accompanied by re-epithelialization. This represents the first pharmacological intervention in treatment of diabetic wounds. Studies to confirm the roles of these MMPs in diabetic wound healing are underway.
Another project involves the design, syntheses, and evaluation of novel antibiotics to treat methicillin-resistant Staphylococcus aureus infections. We have identified two lead templates that show high in vitro activity and promising antibacterial activity in a mouse model of infection. Their pharmacokinetic properties are being optimized. Identification of the target is being pursued by photoaffinity labeling at the whole proteome level, as well as obtaining an X-ray crystal structure of the compounds with the putative target.
Recent Papers
-
Spink, E.; Ding, D.R.; Peng, Z.H.; Boudreau, M.A.; Leemans, E.;
Lastochkin, E.; Song, W.; Lichtenwalter, K.; O'Daniel, P.I.; Testero,
S.A.; Pi, H.L.; Schroeder, V.A.; Wolter, W.R.; Antunes, N.T.; Suckow,
M.A.; Vakulento, S.; Chang, M.; Mobashery, S. "Structure-Activity
Relationship for the Oxadiazole Class of Antibiotics." J. Med. Chem. 2015, 58 (3), 1380-1389.
-
Bouley, R.; Kumarasiri, M.; Peng, Z.H.; Otero, L.H.; Song, W.;
Suckow, M.A.; Schroeder, V.A.; Wolter, W.R.; Lastochkin, E.; Antunes,
N.T.; Pi, H.K.; Vakulento, S.; Hermoso, J.A.; Chang, M.; Mobashery, S.
"Discovery of Antibiotic
(E)-3-(3-Carboxyphenyl)-2-(4-cyanostyryl)quinazolin-4(3H)-one." J. Am. Chem. Soc. 2015, 137 (5), 1738-1741.
-
Ding, D.R.; Lichtenwalter, K.; Pi, H.L.; Mobashery, S.; Chang, M.
"Characterization of a selective inhibitor for matrix
metalloproteinase-8 (MMP-8)." MedChemComm 2014, 5 (9), 1381-1383.
-
O'Daniel, P.I.; Peng, Z.H.; Pi, H.L.; Testero, S.A.; Ding, D.R.;
Spink, E.; Leemans, E.; Boudreau, M.A.; Yamaguchi, T.; Schroeder, V.A.;
Wolter, W.R.; Llarrull, L.I.; Song, W.; Lastochkin, E.; Kumarasiri, M.;
Antunes, N.T.; Espahbodi, M.; Lichtenwalter, K.; Suckow, M.A.;
Vakulenko, S.; Mobashery, S.; Chang, M. "Discovery of a New Class of
Non-beta-lactam Inhibitors of Penicillin-Binding Proteins with
Gram-Positive Antibacterial Activity." J. Am. Chem. Soc. 2014, 136 (9), 3664-3672.
-
Gooyit, M.; Peng, Z.H.; Wolter, W.R.; Pi, H.L.; Ding, D.R.; Hesek,
D.; Lee, M.; Boggess, B.; Champion, M.M.; Suckow, M.A.; Mobashery, S.;
Chang, M. "A Chemical Biological Strategy to Facilitate Diabetic Wound
Healing." ACS Chem. Biol. 2014, 9 (1), 105-110.
-
Gooyit, M.; Song, W.; Mahasenan, K.V.; Lichtenwalter, K.; Suckow,
M.A.; Schroeder, V.A.; Wolter, W.R.; Mobashery, S.; Chang, M. "O-Phenyl
Carbamate and Phenyl Urea Thiiranes as Selective Matrix
Metalloproteinase-2 Inhibitors that Cross the Blood Brain Barrier." J. Med. Chem. 2013, 56 (20), 8139-8150.
Mike and Josie Harper Cancer Research Institute
Mayland Chang
Mayland ChangResearch Professor, Chemistry & Biochemistry
University of Notre Dame
Email: Mayland Chang
Phone: 574-631-6533
Office: 163 Stepan Hall
Mayland Chang, Department of Chemistry and Biochemistry, is working on ways to inhibit cancer metastasis, the spreading of the out-of-control cells to other organs. Although metastasis is a leading reason that cancer becomes fatal, primary tumors rarely kill and often can be treated, no anti-metastatic agent has been commercialized to treat aggressive cancers. Meanwhile, metastasis of breast and prostate cancer, for example, leads to further life-threatening complications that cause tens of thousands of deaths each year.
Building on studies showing that the matrix metal-loproteinases are associated with cancer progression and metastasis in many types of cancers, a few years ago discovered and
synthesized the first prototype selective mechanism-based inhibitor found to be effective in mouse models of prostate cancer metastasis to the bone, breast cancer metastasis to the lungs, and T-cell lymphoma metastasis to the liver. This work has progressed in the direction of compounds that can be used in additional in vivo models for disease, leading to second and third-generation compounds. The researchers are now refining related compounds with the goal of developing selective inhibitors that can advance forward to preclinical development and ultimate entry into clinical trials for the treatment of cancer metastasis.
Five Questions with Mayland Chang
Mayland
Chang, PhD, is bringing scientific discoveries out of academia to the
masses, from new antibiotics to the treatment of skull-crunching head
injuries on the football field. Chang, a faculty member in the Department of Chemistry and Biochemistry, was recently awarded a five year, $5.5 million dollar grant from the National Institute of Allergy and Infectious Diseases (NIAID). She is also the recent recipient of an NFL Charities grant to design and develop therapeutics for the treatment of traumatic brain injury (TBI).
The NIAID grant, a considerably large amount for research grants, will fund translational research aimed at the discovery and development of drugs to fight serious gram-positive bacterial infections such as methicillian resistant Staphylococcus aureus (MRSA). Translational research is described by Chang as “bench to bedside” research, which leads to practical applications in patients.
Chang obtained B.S. degrees in biological sciences and chemistry from the University of Southern California, and a Ph.D. in chemistry from the University of Chicago. She joined Notre Dame in 2003.
Chang recently spoke with ND Today about her research, teaching at Notre Dame, and her hobbies.
ND Today: What does it mean to you to receive the NIAID grant?
Mayland Chang: There is a dearth of research on new antibacterials, as the economic incentives are not there for pharmaceutical companies to pursue discovery and development of antibiotics. Because fewer pharmaceutical companies are focusing on antibacterials (most have abandoned the field), academic institutions have to step up to discover and develop new classes of antibiotics. This grant allows us to do just that.
ND Today: Tell us about your NFL Charities Grant – what type of research will you be doing?
MC: Traumatic brain injury (TBI) is one of the leading causes of death and disability in the industrialized world. A TBI is caused by a bump, blow, or jolt to the head or a penetrating head injury that disrupts the normal function of the brain. The majority of TBIs (75%) are concussions. Concussions are a prominent feature of sports, with 300,000 reported concussions in the U.S. occurring while playing sports. Concussions result from a blow to the head that produces a cascade of neurological events, resulting in reduced blood flow to the brain, brain cell injury, and death.
A contributing factor to these pathological processes is the activation of enzymes called matrix metalloproteinases (MMPs), particularly gelatinases (MMP-2 and MMP-9). There are presently no therapeutics for TBI. Research in the field lacks presently the ability to rescue brain cells after each concussion or any damage to the brain. If a medication could be given after such a damage that rescues the brain cells destined to die that would move the field forward in treatment of TBI significantly. The NFL Charities grant will support groundbreaking research that has the potential for the development of such a treatment for TBI. We have developed a prototype inhibitor, which potently decreases brain damage and hemorrhagic injury. We have synthesized water-soluble inhibitors, which are amenable to intravenous administration, the preferred route of administration for TBI. These results hold outstanding promise for important applications in fighting gelatinase-mediated consequences of brain damage after TBI in patients.NFL funding will open the door for expansion of this project in directions that we hope will lead to treatments for TBI.
ND Today: How did you come to specialize in chemistry?
MC: I grew up in Ecuador and was good in math and science. As a high school student, I only knew of professional careers, such as medicine. I came to the US for college and as an undergraduate at USC I started as a biology major. There was no pre-med major at USC. After taking analytical chemistry as a junior in college, I decided to pursue chemistry. I ended up with a BS in biology and a BS in chemistry. Then I went to graduate school at the University of Chicago and got my PhD as a natural products chemist and post-doc at Columbia University in bioanalytical chemistry. When I was looking for a job, I could not find a position in the industry in natural products chemistry. I ended up doing metabolism of herbicides and insecticides at Dow Chemical. From there I moved to Upjohn. Before moving to Notre Dame, I was COO of University Research Network, Inc., an academic research organization that I established for Wayne State University School of Medicine that facilitated clinical research and provided clinical development services to the pharmaceutical and biotechnology industries.
ND Today: What is the best part about working at Notre Dame?
MC: The opportunity to work with and train talented undergraduate students. Since I came to Notre Dame, I have had nine undergraduates in the lab—four have graduated, one is in grad school at Madison Wisconsin, one is in an MD PhD program at Washington University, one is in an MD program at Loyola, and one is in an MD program at Rochester.
ND Today: Given the very serious nature of your work, what do you like to do to unwind?
MC: Gourmet cooking. Cooking is very much like chemistry. I wanted to be a chef but it was not an acceptable profession [in her home country]. Gardening—pulling weeds relieves stress, and travel—traveling is part of one’s education—it opens the mind to new experiences and cultures. I love to spend time with my cats Misty and Carbon, and watching birds in my backyard. Rain or shine, I feed the birds year-round.
Mayland Chang receives $1.6M American Diabetes Association research award
Mayland ChangThe American Diabetes Association (ADA) announced Tuesday that it is funding a $1.6 million Accelerator Award to Mayland Chang, research professor of chemistry and biochemistry at the University of Notre Dame, to help lower that number. The research award, part of the association’s Pathway Awards program, will provide funding for Chang’s project, “A Strategy to Accelerate Diabetic Wound Repair,” over five years.
Chang’s research is broadly focused on exploring the molecular basis of disease and designing small molecules for therapeutic interventions. She has ongoing projects related to stroke, traumatic brain injury, cancer metastasis and MRSA (methicillin-resistant Staphylococcus aureus). A newer area of work for Chang is to understand why diabetic wounds are so difficult to treat and to develop novel therapeutics to promote wound healing.
Using a mouse model and a novel diagnostic resin that binds to active forms of matrix metalloproteinases (MMPs), proteases involved in tissue remodeling, Chang’s research group found that MMP-9 may cause diabetic wounds and MMP-8 may be involved in wound repair. They also demonstrated that selective pharmacological inhibition of MMP-8 delayed wound repair and inhibition of MMP-9 accelerated wound healing.
Using a combination of research techniques, Chang’s project will identify the mechanisms associated with diabetic wound development, progression and healing; study bacterial colonization in diabetic wounds; and find interventions that expedite the healing process. To achieve these goals, she will validate the roles of MMP-8 and MMP-9 in diabetic wounds, investigate the relevance of these MMPs in human patients, evaluate novel MMP-9 inhibitors and determine the contribution of bacterial infection on wound repair.
“This research project will allow intervention of chronic wounds, a complication of diabetes for which pharmacological clinical recourse is not available,” Chang said. “Our work holds great promise in addressing an unmet medical need.”
Accelerator Awards are designed to support early-career investigators or established researchers who are accomplished in other fields, but would like to apply their expertise to innovative diabetes-related research topics.
Contact: Mayland Chang, 574-631-2965, mchang@nd.edu
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