We propose to develop novel inhibitors of HIV entry that target the highly conserved N-trimer pocket region of HIV gp41. Inhibition of this essential component of HIV's fusion machinery prevents viral entry and the establishment of infection. Our inhibitory peptides are composed of D-amino acids (D-peptides), which are resistant to natural proteases and are predicted to survive in the body for much longer periods of time than traditional L-peptide inhibitors. We will use a combination of structure-based protein design and phage display screening to identify D-peptides with high affinity for the N-trimer and strong antiviral potency in HIV entry assays. We also propose to make multimeric D-peptides that bind to gp41 with greater affinity and antiviral potency. We will determine the high-resolution structures of these D-peptides in complex with their N- trimer target to determine the sources of their potency and to guide the design of improved D-peptides. Potent D-peptide entry inhibitors would be useful both as an additional therapeutic component of an antiretroviral cocktail and for prophylactic microbicide use. These studies will also likely have broad applicability for the development of other D-peptide viral entry inhibitors and for improving our knowledge of D-peptide design in general.
The development of potent protease-resistant D-peptide inhibitors of HIV entry will be useful for the treatment of infected patients (therapeutic agent), as well as the prevention of new infections (prophylactic agent). A better understanding of D-peptide design will stimulate future development of these hardy peptides for diverse applications in scientific research and medicine.
|Jacobsen, Michael T; Erickson, Patrick W; Kay, Michael S (2017) Aligator: A computational tool for optimizing total chemical synthesis of large proteins. Bioorg Med Chem 25:4946-4952|
|Jacobsen, Michael T; Petersen, Mark E; Ye, Xiang et al. (2016) A Helping Hand to Overcome Solubility Challenges in Chemical Protein Synthesis. J Am Chem Soc 138:11775-82|
|Petersen, Mark E; Jacobsen, Michael T; Kay, Michael S (2016) Synthesis of tumor necrosis factor ? for use as a mirror-image phage display target. Org Biomol Chem 14:5298-303|
|Weinstock, Matthew T; Jacobsen, Michael T; Kay, Michael S (2014) Synthesis and folding of a mirror-image enzyme reveals ambidextrous chaperone activity. Proc Natl Acad Sci U S A 111:11679-84|
|Weinstock, Matthew T; Francis, J Nicholas; Redman, Joseph S et al. (2012) Protease-resistant peptide design-empowering nature's fragile warriors against HIV. Biopolymers 98:431-42|
|Francis, J Nicholas; Redman, Joseph S; Eckert, Debra M et al. (2012) Design of a modular tetrameric scaffold for the synthesis of membrane-localized D-peptide inhibitors of HIV-1 entry. Bioconjug Chem 23:1252-8|
|Denton, Paul W; Othieno, Florence; Martinez-Torres, Francisco et al. (2011) One percent tenofovir applied topically to humanized BLT mice and used according to the CAPRISA 004 experimental design demonstrates partial protection from vaginal HIV infection, validating the BLT model for evaluation of new microbicide candidates. J Virol 85:7582-93|
|Welch, Brett D; Francis, J Nicholas; Redman, Joseph S et al. (2010) Design of a potent D-peptide HIV-1 entry inhibitor with a strong barrier to resistance. J Virol 84:11235-44|
|Eckert, Debra M; Kay, Michael S (2010) Stalking influenza. Proc Natl Acad Sci U S A 107:13563-4|
|Eckert, Debra M; Shi, Yu; Kim, Sunghwan et al. (2008) Characterization of the steric defense of the HIV-1 gp41 N-trimer region. Protein Sci 17:2091-100|