Treatments for systemic amyloid diseases have been held back by lack of information on the structures and causes of aggregation of the disease agents. These agents are the elongated, unbranched amyloid fibers formed by proteins having propensity for aggregation. The fibers accumulate in organs which eventually fail. In contrast, the increasingly successful attack on cancer, infectious, and metabolic diseases is rooted in part in the availability of information on the structures of the disease targets, permitting design of effective chemical interventions. In previous work we have developed a procedure for inhibiting the formation of amyloid fibers. This first step is application of our computer algorithm which identifies the short Velcro-like sequence segments that drive formation of amyloid fibers. We have applied this algorithm to find over 100 such segments in disease- related proteins, and have verified that such segments themselves form amyloid fibers, and closely related microcrystals. The second step is X-ray structure determination of these microcrystals, which reveal the atomic basis of fiber formation. The third step is to use the resulting atomic structure as a platform for the design of inhibitors to stop fiber formation. This overall procedure is robus and ready to produce inhibitors of fibers found that cause light-chain (AL) and transthyretin (TTR) systemic amyloidosis. In our research, we will validate particular segments of immunoglobulin light chains and transthyretin as the causes of aggregation, and based on their atomic structures, design inhibitors of aggregation. These inhibitors will be tested for their abilty to halt fiber formation in vitro, and in animal models. In principle, the same methods can be used to develop inhibitors for other systemic amyloid diseases.

Public Health Relevance

Thousands of Americans are afflicted with systemic amyloid diseases, in which particular proteins aggregate into fibers that accumulate in vital organs, causing them to fail. We have developed general methods for inhibiting amyloid fiber formation. We will apply these structure-based methods to design, synthesize, and test inhibitors that can stop fiber formation, and hopefully halt disease progression.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Project (R01)
Project #
Application #
Study Section
Macromolecular Structure and Function B Study Section (MSFB)
Program Officer
Velazquez, Jose M
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of California Los Angeles
Schools of Medicine
Los Angeles
United States
Zip Code
Saelices, Lorena; Pokrzywa, Malgorzata; Pawelek, Katarzyna et al. (2018) Assessment of the effects of transthyretin peptide inhibitors in Drosophila models of neuropathic ATTR. Neurobiol Dis 120:118-125
Brumshtein, Boris; Esswein, Shannon R; Sawaya, Michael R et al. (2018) Identification of two principal amyloid-driving segments in variable domains of Ig light chains in systemic light-chain amyloidosis. J Biol Chem 293:19659-19671
Saelices, Lorena; Sievers, Stuart A; Sawaya, Michael R et al. (2018) Crystal structures of amyloidogenic segments of human transthyretin. Protein Sci 27:1295-1303
Brumshtein, Boris; Esswein, Shannon R; Salwinski, Lukasz et al. (2015) Inhibition by small-molecule ligands of formation of amyloid fibrils of an immunoglobulin light chain variable domain. Elife 4:e10935
Saelices, Lorena; Johnson, Lisa M; Liang, Wilson Y et al. (2015) Uncovering the Mechanism of Aggregation of Human Transthyretin. J Biol Chem 290:28932-43
Brumshtein, Boris; Esswein, Shannon R; Landau, Meytal et al. (2014) Formation of amyloid fibers by monomeric light chain variable domains. J Biol Chem 289:27513-25