Peptides as biological signaling molecules and novel drugs

Lectures: 1 session / week, 2 hours / session

There are no formal prerequisites, but some knowledge of genetics, biochemistry and cell biology is expected. Ideally, candidates have successfully taken at least one of the following classes:

7.03 Genetics

7.05 General Biochemistry

7.06 Cell Biology

7.28 Molecular Biology

All living cells possess a machinery for peptide synthesis, secretion, and posttranslational modifications. An enormous structural and functional diversity of peptides is generated by use of this cellular machinery. Peptides are broadly used as signal molecules for intercellular communication in prokaryotes, plants, fungi, and animals. Peptide signals in animals include vast numbers of peptide hormones, growth factors and neuropeptides. Some of the best known examples are enkephalins (which help us sense pain), somatotropin (which helps us grow), and insulin and glucagon (both of which regulate our blood glucose levels). Similarly in plants, peptide signals such as CLAVATA3 play important roles in development. Peptides are also used by living organisms as components of their host defense systems.

What determines the functional specificity of each peptide? How do these small polymers of amino acids survive hostile protein-digesting enzymes? How are they able to communicate with their specific peptide receptors or interacting proteins for proper function? In this course, we will learn about molecular bases of peptide signaling.

In addition, peptides potentially can be used as potent broad-spectrum antibiotics and hence might define novel therapeutic agents. For example, antimicrobial peptides (AMPs) are low molecular weight proteins with broad spectrum antimicrobial activity against bacteria, viruses, and fungi and are found among all classes of life. The ability of these natural molecules to kill multidrug-resistant microorganisms has gained them considerable attention and clinical interest, since multidrug-resistant microorganisms have developed resistance to multiple antimicrobial agents and are difficult to treat with available antibiotics. One of the most notorious examples is MRSA, deadly strains of methicillin-resistant Staphylococcus aureus. Infections with these pathogenic bacteria are untreatable with known antibiotics like gentamicin, streptomycin and kanamycin. Some antimicrobial peptides can kill methicillin-resistant S. aureus strains, making them promising future drugs.

In this class, we will discuss AMPs, their biological functions, mechanisms of action, and applicability as therapeutic agents. Students will learn about various human defense peptides, such as defensins, and about plant peptides involved in symbiosis, such as nodule-specific cysteine-rich peptides. We will consider techniques to detect, quantify and modify peptides. We will also discuss experimental methods such as high-performance liquid chromatography (HPLC) and liquid chromatography coupled with mass spectroscopy (LC-MS) used for quantification of small molecules such as peptides. We will focus on the primary research literature, and students will learn how to read and critique research papers. Additionally, we will visit Cubist Pharmaceuticals, a pharmaceutical company based in Lexington, MA, which is developing peptides as drugs for various pathological conditions, such as complicated urinary tract infections.

The course meets weekly for 2 hours. For each class, students must read two research papers assigned by the instructor. The instructor will spend the last 15 minutes of every class introducing the next week's topic. Students are encouraged to contact the instructor with questions or concerns about any aspect of the papers before each class. To facilitate discussion, students must submit three questions related to the papers to the instructor prior to each class. Questions can be about background, methods, data or overall interpretation of the paper. Active participation in class discussion is a must for this course. Students also need to complete one written and one oral assignment.

The goals of this course are:

This course will be graded Pass / Fail. To pass this course, it is essential to read the papers, email three questions to the instructor prior to each session, actively participate in the class discussions, and satisfactorily complete the assignments.

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