Getting clotting factors to last longer in the blood

The BCH blog Vector talks about the progress of rFIXFc, a recombinant hybrid of Factor IX and an Fc receptor fragment, a new long lasting clotting factor which recently passed a phase 3 clinical trial. The technology is the result of a collaboration Wayne Lencer, a researcher at Boston Children’s Hospital, Richard Blumberg from Brigham and Women’s Hospital (BWH) and Associate Professor of Biology Neil Simister from Brandeis. We’re all excited to see this technology emerge from the labs, and progress to the point where it’s poised to make a significant impact in the lives of hemophilia patients.

An alternative to scuba diving

Many promising medicinal agents (anti-cancer, anti-bacterial, anti-viral and anti-fungal) have been discovered among the diverse molecules produced by marine organisms. However, scuba-diving to harvest sponges and algae is not usually a practical way of obtaining usable quantities of these compounds, especially if they are present only in trace quantities in the source organisms.

A recently published paper in Organic Letters from the laboratory of Assistant Professor of Chemistry Isaac Krauss is the first to present a synthetic laboratory approach to the preparation of the bromophycolides, originally isolated from Callophycus Serratus, a red algae which was collected off the coast of Fiji. Although these compounds were shown to posses anti-tumour, anti-HIV and anti-malarial properties, algae collected in a second expedition to Fiji apparently contained none of the natural product (hence the desirability of a laboratory synthesis). The bromophycolides are a structurally unique family of natural products containing brominated asymmetric carbon centers and large 19-membered rings. This paper illustrates the preparation of the bromophycolide A and D ring system in high enantiomeric purity via a short (9-step) synthetic sequence.

Susan Band Horwitz (PhD ’63) receives AACR Lifetime Achievement Award

Susan Band Horwitz, Ph.D., will receive the Eighth AACR Award for Lifetime Achievement in Cancer Research. Horwitz is being recognized for pioneering research in the mechanism of the anticancer drug Taxol and for contributions to the understanding of how this microtubule-stabilizing drug arrests cell division, which eventually leads to cell death, especially of cancer cells.

Horwitz received a bachelor’s from Bryn Mawr, then came to Brandeis to do her graduate studies. According to a profile in PNAS by Tinsley H. Davis,

“At that time, there were few graduate schools that were very receptive to women,” [Horowitz] recalls. “Women were not very prominent on the faculty or in the student body.” One university stood out from the others, however. Brandeis University (Waltham, MA) had just started its graduate program in biochemistry. “Brandeis was a new and exciting place, and the people there wanted it to succeed,” says Horwitz, “yet it also had a relaxed atmosphere that was really perfect for me.”

Once at Brandeis, Horwitz worked with Nathan Kaplan, chairman of the newly formed Biochemistry Department. Her Ph.D. dissertation (1963) involved bacterial metabolism of sugar alcohols.

While juggling raising children and doing part-time postdoctoral research (some things haven’t changed so much over the years!), Horwitz became interested in pharmacology and anticancer agents. She joined the faculty at Albert Einstein College of Medicine in 1970, where she has remained since, currently serving as the Rose C. Falkenstein Professor of Cancer Research and co-chair of the department of molecular pharmacology.

Horwitz’s academic career has been vastly productive, in terms of research, publications and awards, but perhaps more significantly in terms of her research’s impact on millions of cancer patients worldwide. Her current research focuses on new natural products with similar mechanism to Taxol, looking for ways to enhance therapeutic value and to avoid drug resistance.

The AACR Award for Lifetime Achievement in Cancer Research was established in 2004 to honor an individual who has made significant fundamental contributions to cancer research, either through a single scientific discovery or a body of work. These contributions, whether they have been in research, leadership or mentorship, must have had a lasting impact on the cancer field and must have demonstrated a lifetime commitment to progress against cancer. Horwitz will receive the award at the Opening Ceremony of the AACR 102nd Annual Meeting.

Andy Berglund (PhD ’97) to talk about Myotonic Dystrophy

Professor Andy Berglund from the Institute of Molecular Biology at U. Oregon will be on campus on Wednesday, Jan. 19 to talk about Understanding Protein-RNA Interactions in Myotonic Dystrophy and a Small Molecule Approach to Target the Toxic Element in this Disease at the year’s Kaplan Lecture in the Joint Biology/Biochemistry Semester Series. Berglund received his Ph.D. in Biochemistry from Brandeis in 1997, working on RNA processing, yeast splicing more specifically, in Michael Rosbash’s lab. He did a seminal piece of work for his thesis, which showed that the yeast branchpoint binding protein BBP, also known as SF1 in mammals, recognizes the yeast branchpoint sequence UACUAAC. After doing postdocs with Steve Schultz and Tom Cech at U. Colorado, Berglund assumed a faculty position at U. Oregon in 2002, where he is now an Associate Professor. His current research aims in part to understand and develop therapies for a specific form of human muscular dystrophy, which is called myotonic dystrophy. This disease is caused by expression of a toxic RNA,  which interacts with the RNA binding protein muscleblind and thereby indirectly interferes with RNA splicing. So Berglund has continued his interest in splicing, but with this more human disease focus. Indeed, his lab has identified small molecules that could potentially be used to counter these splicing defects .

The Kaplan Lecture is held annually to honor the memory of Nate Kaplan, who was the first chair of the Graduate Department of Biochemistry at Brandeis, playing a huge role in the emergence of Brandeis as a major research university. Kaplan lecturers are members of the Brandeis Biochemistry community who have gone on to distinguished research careers elsewhere. The talk will take place in Gerstenzang 121 at 4:00 pm, Brandeis community members are invited to attend.

Novel IMPDH inhibitors are candidates for antibacterial drugs

The rise of multiply drug resistant bacteria creates an urgent need for new antibiotics and novel antibiotic targets.  IMPDH, a key enzyme in the biosynthesis of RNA/DNA precursors, is a target for cancer therapy that has not been exploited in antibiotic development. In their recent paper in Chemistry & Biology entitled Structural determinants of inhibitor selectivity in prokaryotic IMP dehydrogenases, Prof. Lizbeth Hedstrom and Brandeis postdocs Deviprasad Golapalli, Iain MacPherson and Suresh Gorla show that selective inhibitors of IMPDH from the protozoan parasite Cryptosporidium parvum also exhibit antibacterial activity. This work could lead to novel treatments for a wide variety of bacterial infections, including some of the most devastating and troubling human pathogens: Mycobacterium tuberculosis, drug-resistant Staphylococcus aureus (e.g. MRSA and VRSA), drug resistant Streptococcus pneumoniae and select agents such as Bacillus anthracis, Burkholderia mallei/pseudomallei and Francisella tularensis.  Importantly, these compounds will spare some commensal bacteria, which should decrease side effects and slow the rise of resistance.  This work suggests that IMPDH-targeted inhibitors can be developed into a new class of broader spectrum antibiotics.

“All you need is a cow and a centrifuge…”

“…to harvest enough oocysts to infect a small city”.

Read more about the Hedstrom lab‘s research on Cryptosporidium in this press release from FASEB.

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