Whereas the conformational preferences and peptide-stabilizing properties of trisubstituted dehydroamino acids (?AAs) such as ?Ala, ?Phe, ?Abu, and ?Leu are established, bulky ?AAs with tetrasubstituted alkenes such as ?Val, E- and Z-?Ile, and dehydroethylnorvaline (?Env) have scarcely been studied. Bulky tetra- substituted ?AAs should have a greater influence on peptide structure and stability than trisubstituted ?AAs due to their higher levels of A1,3 strain causing increased rigidity and more stable folded states. The objective of this proposal is to define the impact of bulky ?AAs on peptide structure and stability while probing the bioactivity of a natural product that contains these residues. The hypothesis is that new methods for synthesizing bulky ?AAs will facilitate construction of peptides with well-defined conformations, improved stability to proteases, and in some cases potent biological activity. The rationale for this idea is that the fundamental knowledge obtained from this study will inform the future design and synthesis of bulky-?AA-containing peptides for addressing important problems in chemical biology and medicinal chemistry. The hypothesis will be tested by pursuing two Specific Aims.
Aim 1 involves identifying a simplified analogue of yaku?amide A (YA) that closely mimics its bioactivity. YA is a rare marine natural product with potent anticancer activity and a novel mode of action. It contains ?Val, E-?Ile, and Z-?Ile. YA will be synthesized using novel methodology designed for the stereoselective construction of bulky ?AAs. Molecular modeling will be employed to identify simplified analogues with conformations that closely resemble those of YA. These analogues will be synthesized in 35?40% fewer steps than were required by Inoue to construct a diastereomer of YA, then screened alongside YA in order to identify the compound that most closely mimics its anticancer properties.
Aim 2 entails devising rules for including bulky ?AAs in secondary structures and evaluating their ability to protect peptides from proteolysis. Validated model peptides will be used to determine the propensities of ?Val, ?Env, E-?Ile, and Z-?Ile to reside in ?-turns, ?-helices, and ?-sheets. Then, analogues of the anti-HIV drug enfuvirtide containing bulky ?AAs in the C-terminal region will be constructed using new SPPS-based methodology and evaluated for proteolytic stability and antiviral efficacy. The approach is innovative because it employs new synthetic strategies that will for the first time enable efficient access to bulky ?AA-containing peptides, thereby allowing important questions to be answered and new horizons in peptide chemistry to be reached. The significance of the proposed research lies in its ability to facilitate a host of important future studies of bioactive peptides. Such studies could include determining the biological target of YA, developing new therapeutic peptides for HIV/AIDS, designing bulky ?AA-containing peptides with proteolytic stability that are capable of disrupting protein?protein interactions with relevance to human diseases, and studying the properties of other bulky ?AAs including those with cycloalkyl or fluorinated alkyl groups.

Public Health Relevance

This project involves the incorporation of bulky dehydroamino acids into bioactive peptides for the purpose of stabilizing them against degradation by proteases. The targeted peptides have potent activity against cancer and HIV. With the potential of leading to new and improved therapeutic agents for these and other diseases, this project is highly relevant to public health and to the mission of the NIH.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Academic Research Enhancement Awards (AREA) (R15)
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Fabian, Miles
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Brigham Young University
Schools of Arts and Sciences
United States
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Jalan, Ankur; Kastner, David W; Webber, Kei G I et al. (2017) Bulky Dehydroamino Acids Enhance Proteolytic Stability and Folding in ?-Hairpin Peptides. Org Lett 19:5190-5193
Castle, Steven L (2017) Remodeling vancomycin yields a victory in the battle against bacteria. Proc Natl Acad Sci U S A 114:6656-6657