Targeted therapies are based on diseased cells having characteristics that distinguish them from healthy cells. Several pathological states including cancer, ischemia, and inflammation are characterized by acidosis. We propose to exploit acidosis to develop new technologies for targeted therapies. We have recently developed new peptides that insert into membranes only in acidic conditions. Preliminary data show that these acidity- triggered rational membrane (ATRAM) peptides have favorable biophysical properties and target cells in a pH- responsive fashion. We will determine the optimal peptide sequence in the context of the transverse asymmetry in lipid composition found in most cellular membranes. Next, we will determine the pKa of the residues responsible for triggering membrane insertion under acidic conditions. This will be instrumental in elucidating the molecular mechanism of ATRAM peptides. We have evolved the design of the ATRAM peptides to design bifunctional peptides that have the potential to modulate the activity of the EphA2 receptor. EphA2 is involved in mediating invasion and metastasis in different tumor types. Our data suggest that these peptides are soluble, but are also able to insert into membranes and activate the EphA2 receptor. We will study peptide control over the clustering of the EphA2 receptor. A set of peptides of different sequences will be used as a tool to determine the conformational changes associated to the formation of the membrane clusters of EphA2, leading to receptor activation. This multidisciplinary study will lead to a molecular understanding of the mode of action of these peptides. This knowledge will provide important clues to develop future therapeutic technologies that specifically target the acidosis of diseased tissues.

Public Health Relevance

Many diseases including arthritic inflammation, cardiac ischemia, and cancer are characterized by acidity. The proposed research describes the discovery of peptides that specifically target cells when acidosis is present. We propose these studies can lead to the development of new tools for therapies specifically targeting acidosis.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
3R01GM120642-02S1
Application #
9718801
Study Section
Biochemistry and Biophysics of Membranes Study Section (BBM)
Program Officer
Nie, Zhongzhen
Project Start
2016-09-01
Project End
2021-08-31
Budget Start
2017-09-01
Budget End
2018-08-31
Support Year
2
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Tennessee Knoxville
Department
Biochemistry
Type
Schools of Arts and Sciences
DUNS #
003387891
City
Knoxville
State
TN
Country
United States
Zip Code
37916
Usery, Rebecca D; Enoki, Thais A; Wickramasinghe, Sanjula P et al. (2018) Membrane Bending Moduli of Coexisting Liquid Phases Containing Transmembrane Peptide. Biophys J 114:2152-2164
Alves, Daiane S; Westerfield, Justin M; Shi, Xiaojun et al. (2018) A novel pH-dependent membrane peptide that binds to EphA2 and inhibits cell migration. Elife 7:
Kaliszewski, Megan J; Shi, Xiaojun; Hou, Yixuan et al. (2018) Quantifying membrane protein oligomerization with fluorescence cross-correlation spectroscopy. Methods 140-141:40-51
Zhang, Xiaoyu; Alves, Daiane S; Lou, Jinchao et al. (2018) Boronic acid liposomes for cellular delivery and content release driven by carbohydrate binding. Chem Commun (Camb) 54:6169-6172
Scott, Haden L; Westerfield, Justin M; Barrera, Francisco N (2017) Determination of the Membrane Translocation pK of the pH-Low Insertion Peptide. Biophys J 113:869-879
Shi, Xiaojun; Hapiak, Vera; Zheng, Ji et al. (2017) A role of the SAM domain in EphA2 receptor activation. Sci Rep 7:45084
Karabadzhak, Alexander G; Petti, Lisa M; Barrera, Francisco N et al. (2017) Two transmembrane dimers of the bovine papillomavirus E5 oncoprotein clamp the PDGF ? receptor in an active dimeric conformation. Proc Natl Acad Sci U S A 114:E7262-E7271