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Dr. John 'Jay' Schneekloth


Dr. John 'Jay' Schneekloth
Chemical Genetics
301-228-4620

Postdoctoral positions are available for highly talented and motivated chemical biologists to join the Schneekloth laboratory. Ideal candidates will have an interest/experience in ubiquitin-like signaling or RNA-binding small molecules, though highly qualified candidates of any background in chemical biology will be considered. Applicants must be near completion or have recently completed a Ph.D. Interested candidates should contact Dr. Schneekloth directly at schneeklothjs@mail.nih.gov and include CV, research summary, and 3 references.

Research Summary

Small Molecule Probes of Protein Sumoylation
The Small Ubiquitin-like Modifier (SUMO) is a ubiquitin-like posttranslational modification. Protein sumoylation is tightly linked with gene expression, as many of the known substrates for sumoylation are transcription factors. Furthermore, the aberrant regulation of sumoylation is linked to a number of cancers. Our laboratory has developed a novel electrophoretic mobility shift assay we are using in a high throughput screen of natural product extracts to identify naturally occurring small molecule sumoylation inhibitors. As a complementary approach, we are using fragment-based inhibitor design approaches to develop synthetic inhibitors of sumoylation. In addition, we have developed several synthetic substrates of sumoylation with the aim of gaining insight into substrate recognition and to identify active site-directed inhibitors. A major goal of this project is to establish a structural basis for chemical inhibition of sumoylation, and to gain insight into the structure and function of sumoylation enzymes and their role in cancer biology.

Identification of RNA- and DNA-binding Small Molecules Using Small Molecule Microarrays
The identification of selective RNA- and DNA-binding small molecules has been a longstanding challenge for chemical biology. Our approach to this problem is to use small molecule microarrays as a screening technology. We have assembled a library of 20,000 compounds that are used to screen diverse nucleic acid targets such as RNA hairpins and DNA G-quadruplexes. Most recently, we reported the identification of a druglike compound that binds to the HIV transactivation response (TAR) hairpin. This compound is not cationic, selectively binds to TAR in the context of the entire HIV 5'UTR, and rescues lymphoblastic cells from HIV-mediated cytopathicity without any observable toxicity. Future goals for this project involve the identification of small molecules that selectively interact with a broad variety of therapeutically relevant RNA targets.
PublicationsPatents
1 - 5 of 36 results

1)  Abulwerdi Fardokht A, Xu Wenbo, Ageeli Abeer A, Yonkunas Michael J, Arun Gayatri, Nam Hyeyeon, Schneekloth John S, Dayie Theodore Kwaku, Spector David, Baird Nathan, Le Grice Stuart F J.
Selective Small-Molecule Targeting of a Triple Helix Encoded by the Long Noncoding RNA, MALAT1.
ACS Chem. Biol. 14: 223-235, 2019. [Journal]

2)  Connelly Colleen M, Numata Tomoyuki, Boer Robert E, Moon Michelle H, Sinniah Ranu S, Barchi Joseph J, Ferré-D'Amaré Adrian R, Schneekloth John S.
Synthetic ligands for PreQ1 riboswitches provide structural and mechanistic insights into targeting RNA tertiary structure.
Nat Commun. 10: 1501, 2019. [Journal]

3)  Calabrese David R, Chen Xiang, Leon Elena C, Gaikwad Snehal M, Phyo Zaw, Hewitt William M, Alden Stephanie, Hilimire Thomas A, He Fahu, Michalowski Aleksandra M, Simmons John K, Saunders Lindsey B, Zhang Shuling, Connors Daniel, Walters Kylie J, Mock Beverly A, Schneekloth John S.
Chemical and structural studies provide a mechanistic basis for recognition of the MYC G-quadruplex.
Nat Commun. 9: 4229, 2018. [Journal]

4)  Boer Robert E, Schneekloth John S.
Targeting Mammalian Translational Inhibition with Tetracyclines.
Cell Chem Biol. 25: 1437-1438, 2018. [Journal]

5)  Yan Pengcheng, Ritt Daniel A, Zlotkowski Katherine, Bokesch Heidi R, Reinhold William C, Schneekloth John S, Morrison Deborah K, Gustafson Kirk R.
Macrophilones from the Marine Hydroid Macrorhynchia philippina Can Inhibit ERK Cascade Signaling.
J. Nat. Prod. 81: 1666-1672, 2018. [Journal]