- Ph.D., University of California, San Diego, 1995
Research in the Natural Products Chemistry Section focuses on the discovery and development of new classes of molecules that are effective in preventing infections by bacterial and viral pathogens with an emphasis on compounds effective against drug-resistant bacteria.
Our lab carries out interdisciplinary research aimed at the discovery of biologically active natural products, also known as secondary metabolites; seeks to understand basic principles involved in protein-carbohydrate interactions and how these can be exploited to engineer therapeutics; and designs and synthesizes small molecules and peptides that block, or can be used to probe the events that lead to viral entry.
Natural products chemistry
We subscribe to the notion that as a result of millions of years of evolutionary pressure to effect biology, natural products represent an ideal starting point for identifying new inhibitors of macromolecular receptors and biological processes. Ongoing projects, approaches, and interests include isolation and complete structure elucidation of natural products that kill drug resistant bacteria and block virus infection. To elucidate chemical and 3-dimensional structures of inhibitors we rely on multidimensional nuclear magnetic resonance (NMR) and modern spectroscopic techniques. NMR methods are especially powerful because they can be used to identify precise targets on proteins, or important structural features of inhibitors that account for activity. A variety of approaches are used to identify targets or determine mechanisms of action, including mutagenesis and genome sequencing, and cell based and functional assays.
Protein-carbohydrate recognition and its role in infectious diseases
Protein-carbohydrate interactions play critical roles in countless biological processes and recognition events as diverse as fertilization, leukocyte homing during the course of inflammation, and trafficking of tumor cells during metastasis. Not to be forgotten all microbes and many viruses display unique glycan structures, carbohydrate-binding proteins, or both on their outer membranes or cell surfaces.
Our efforts focus on the discovery of novel carbohydrate-binding proteins isolated from understudied sources, such as cyanobacteria and invertebrates, and comprehensive studies of their carbohydrate specificity and recognition. This is accomplished using glycan profiling and biophysical techniques, evaluation of antimicrobial or antiviral activities, and high-resolution structure determination by NMR or x-ray crystallography. Many protein-carbohydrate interactions are multivalent. A larger goal in our research aims to define at a level that would satisfy chemists, how these multivalent interactions take place and how they manifest in specificity.
Peptide and protein inhibitors of HIV-1 entry
The initial step of HIV infection involves stepwise binding of the surface envelope glycoproteins, gp120/gp41, to cellular receptors, CD4 and CCR5 or CXCR4. Peptides and proteins derived from these receptors can block HIV-1 fusion, provide valuable mechanistic probes for studying fusion events, and elicit antibodies directed toward these molecules. Projects in this area include engineering stable trimeric gp41 N-helices as inhibitors and immunogens, chemical synthesis of post-translationally modified coreceptor-derived peptides and analogs, and high-resolution structural studies of each.
Applying our Research
Infectious diseases take an enormous toll on human health. An understanding of the mechanisms that lead to infection by pathogens, at the molecular level and in high-resolution, can explain how inhibitors are able to block infection. This knowledge can be used to develop new medicines for human health.
Need for Further Study
Unanswered questions relevant to the field of antibiotic discovery and carbohydrate recognition:
- Can drug resistant bacteria be killed through non-traditional targets, and are these targets 'druggable'?
- What is the barrier that prevents the vast majority of small molecules to cross the outer membrane of Gram-negative bacteria? Answers to these questions may facilitate development of new antibiotics.
- How do lectins achieve precise specificity, and can we use their architecture to engineer therapeutics?
- Chrysophaentins are competitive inhibitors of FtsZ and inhibit Z-ring formation in live bacteria.
- Keffer JL, Huecas S, Hammill JT, Wipf P, Andreu JM, Bewley CA.
- Bioorg Med Chem (2013 Sep 15) 21:5673-8. Abstract/Full Text
- Trimeric HIV-1-Env Structures Define Glycan Shields from Clades A, B, and G.
- Stewart-Jones GB, Soto C, Lemmin T, Chuang GY, Druz A, Kong R, Thomas PV, Wagh K, Zhou T, Behrens AJ, Bylund T, Choi CW, Davison JR, Georgiev IS, Joyce MG, Kwon YD, Pancera M, Taft J, Yang Y, Zhang B, Shivatare SS, Shivatare VS, Lee CC, Wu CY, Bewley CA, Burton DR, Koff WC, Connors M, Crispin M, Baxa U, Korber BT, Wong CH, Mascola JR, Kwong PD.
- Cell (2016 May 5) 165:813-26. Abstract/Full Text
Research in Plain Language
Our lab employs a wide range of methods to identify and study chemical compounds found in the natural world that can be useful medically. We have a particular interest in engineering compounds that prevent HIV-1 infection by blocking the virus from fusing into healthy cells, and in discovering new natural products that prevent drug-resistant bacterial infections.