Friedler Assaf

Professor of Chemistry
Peptide chemistry. Protein protein interactions. Biophysical chemistry. Medicinal chemistry. Chemical biology.
• Ph.D, 2000, the Hebrew University of Jerusalem
• B.Sc., 1994, the Hebrew University of Jerusalem
Philadelphia 311
02 6585 746
Research Focus: 

Our group is interested in using peptides for the quantitative biophysical and structural analysis of protein-protein interactions (PPI) in health and disease. Based on this, we develop lead compounds that modulate PPI for therapeutic purposes. Peptides serve as major tools both for studying PPI and for modulating them (by inhibition or activation). Some examples for our research are:

1.         Using peptides to modulate the oligomeric state of proteins1,2. Many disease-related proteins are in equilibrium between active and inactive oligomeric states. Specific binding of peptides to one of the oligomeric states of such protein should result in stabilization of this state and consequently in shift of the oligomerization equilibrium towards it. We term peptides with such activity as “shiftides”, and they can be utilized therapeutically in two manners: (i) inhibiting a protein by shiftides that bind preferentially to its inactive oligomeric state and stabilize it; (ii) activating a protein by shiftides that bind preferentially to the active oligomeric state and stabilize it. Examples for shiftides developed in our lab are for the HIV-1 integrase 2,3 and other HIV-1 and cancer-related proteins.

2.         Development of new synthetic methods for peptide modifications. We are developing new methods for peptide synthesis and stabilization, mainly peptide cyclization. We developed a new approach for peptide cyclization during solid phase synthesis under highly acidic conditions, and applied it for improving our HIV-1 integrase inhibitors4. Our approach involves simultaneous in situ deprotection, cyclization and TFA cleavage of the peptide, which is achieved by forming an amide bond between a lysine side chain and a succinic acid linker at the peptide N-terminus. The reaction proceeds via a highly active succinimide intermediate, which was isolated and characterized. Our new methodology is applicable for the formation of macrocycles in solid phase synthesis of peptides and organic molecules. We also developed a new general N-acetylation method for solid phase synthesis5. Malonic acid is used as precursor and the reaction proceeds by in situ formation of a reactive ketene intermediate at room temperature.

3.         Intrinsically disordered proteins: About one third of the genome encodes for intrinsically disordered proteins (IDPs) or disordered regions in proteins (IDRs). These lack stable tertiary structures and are composed of a large ensemble of extended and flexible conformations interchanging dynamically. IDPs are involved in many human diseases, making them attractive targets for drug design. However, more than 90% of current drug targets are enzymes or receptors and IDPs still cannot be targeted due to the lack of specific binding pockets for small molecules. Our research focuses on how intrinsic protein disorder regulates protein activity with the ultimate goal of setting IDPs and IDRs as therapeutic targets. Some examples include: (1) the pro-apoptotic ASPP2 protein 6,7; (2) The HIV-1 Rev protein8; (3) the centrosomal STIL protein, which is upregulated in cancer9.

4.         Peptide array screening: our lab is expert in developing methods for screening peptide arrays and in using peptide arrays both for identifying protein interaction sites and for performing high throughput SAR studies.10,11




Selected Publications: 

1. Gabizon, R. and Friedler A. (2014) Allosteric modulation of protein oligomerization: an emerging approach to drug design. Front Chem.;2:9

2. Hayouka, Z., et al., (2007) Inhibiting HIV-1 integrase by shifting its oligomerization equilibrium. Proc Natl Acad Sci U S A,. 104(20): p. 8316-21.

3. Hayouka, Z., et al., (2010) Cyclic peptide inhibitors of HIV-1 integrase derived from the LEDGF/p75 protein. Bioorg Med Chem,. 18(23): p. 8388-95.

4. Chandra K, Roy TK, Shalev DE, Gilon C, R. Gerber RB and Friedler A (2014) A tandem in situ peptide cyclization during TFA cleavage; Angew Chem Int Ed Eng, 53(36):9450-5

5. Chandra K, Roy TK, Naoum JN, Gilon C, Gerber RB, Friedler A. (2014) A highly efficient in situ N-acetylation approach for solid phase synthesis.; Org Biomol Chem. 12(12):1879-84

6 . Rotem, S. et al. The structure and interactions of the proline-rich domain of ASPP2. (2008) J Biol Chem 283, 18990-1899; Rotem-Bamberger, S., Katz, C. & Friedler, A. (2013) Regulation of ASPP2 interaction with p53 core domain by an intramolecular autoinhibitory mechanism. PLoS One 8, e58470,

7. Katz C.  , Benyamini H.  , Rotem S.  , Lebendiker M.  , Danieli T.  , Dines, M.  , Bronner, V.  , Bravman, T.  , Rudiger S.   and Friedler A.   (2008): Molecular Basis of the Interaction Between the Anti-Apoptotic Bcl-2 Family Proteins and the Pro-Apoptotic Protein ASPP2; Proc. Natl. Acad. Sci. USA, 105(34):12277-82

8. Faust, O. et al. (2014) A role of disordered domains in regulating protein oligomerization and stability Chem Comm 18;50(74)

9. Amartely, H. et al. (2014) The STIL protein contains intrinsically disordered regions that mediate its protein-protein interactions. Chem Comm, 50(40):5245-7.

10. Katz C  , Levy-Beladev L  , Rotem-Bamberger S  , Rito T  , Rüdiger SG  , Friedler A.   (2011) Studying protein-protein interactions using peptide arrays. Chem Soc Rev. 40(5):2131-45

11. Gabizon R  , Faust O  , Benyamini H  , Nir S  , Loyter A   and Friedler A   (2012) Structure activity relationship studies using peptide arrays: the example of the HIV-1 Rev - Integrase interaction; Med Chem Comm, 4, 252-259.