Stefan Sarafianos, PhD

Professor, Laboratory of Biochemical Pharmacology, Department of Pediatrics, School of Medicine

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Graduate Programs

Full Member - Biochemistry, Cell and Developmental Biology
Full Member - Microbiology and Molecular Genetics
Full Member - Molecular and Systems Pharmacology

Education

Postdoctoral, Rutgers University, Center for Advanced Biotech & Medicine (E. Arnold), 1999
Postdoctoral, University of Medicine & Dentistry of New Jersey (Modak), 1995
PhD, Georgetown University, 1993
BS, Patras University, 1986

Contact Information

Email: ssarafi@emory.edu

Phone: 404-727-9579

Address:
Health Sciences Research Building, E470 1760 Haygood Drive Atlanta, GA 30322

Our research aims to unravel fundamental mechanisms of drug action, drug resistance, and other aspects of the life cycles of viruses that cause severe diseases. In turn, we apply this knowledge in the design of novel antiviral approaches toward the development of therapeutics. Our drug discovery efforts leverage collaborations with world leading laboratories and use of state-of-the-art multidisciplinary tools, including virological approaches, microscopy methods (super-resolution, single-molecule, and confocal approaches), structural (crystallographic and now cryo-electron microscopy), biochemical (pre-steady state kinetics), biophysical (thermophoresis, surface plasmon resonance), high-throughput and high-content screening as well as structure-based drug design (molecular modeling). Our efforts have led to the development of EFdA, a highly promising long-acting antiviral, currently in Phase III clinical trials for the treatment of HIV infection. Additional funded research interests include SARS-CoV-2, Hepatitis B Virus (HBV), MonkeyPox Virus (MPOXV, Nipah Virus (NiV). Other viruses studied include Ebola Virus, Hepatitis C Virus (HCV), Zika Virus, Foot-and-Mouth Disease Virus (FMDV). For detailed description of currently funded research, please follow link: https://projectreporter.nih.gov/Reporter_Viewsh.cfm?sl=12EECC0B4C8ECFDE7598B8961CAA4A01A2FFCEB861BF

Some projects (with selected publications) are also listed below:

-Development of EFdA as a weekly oral dosing and once-yearly slow-release dosing anti-HIV drug (PNAS 113:9274-9, 2016; J Biol Chem. 289: 24533-48, 2014) (with Dr. Mitsuya, NIH, Kumamoto Univ). Studies continue on the mechanism of EFdA activation and resistance in clinical settings (R01 AI076119).

-Virological, biochemical, and structural studies of HIV capsid with host factors and capsid-targeting antivirals (Science 349: 99-103, 2015) (with Z. Wang, Univ of Minnesota) (R01 AI120860). -Molecular mechanisms of HIV Drug resistance (Antimicrob Agents Chemother. 61, 2017; Viruses. 6 (9), 3535-3562, 2015) (with U Neogi and A Sonnerborg, Karolinska Institutet) (R01 GM118012).

-Novel antiviral discovery and drug resistance studies for SARS-CoV-2. Using our recently developed replicon systems, we are screening nucleoside analog compounds for the discovery of anti-SARS-CoV-2 hits, which upon hit-to-lead optimization can become COVID-19 drug candidates (R01 AI167356). To explore the mechanisms of resistance to the antiviral component of Paxlovid, nirmaltrevir (NIR), we have designed mutations in our replicons to impair NIR binding (bioRxiv. 2023 Jan 3:2022.12.31.522389).

-Novel antivirals for Mpox Virus (MPXV). Through our collaboration with the lab of Dr. Haian Fu, we are performing high throughput screening (HTS) and high content screening (HCS) using Modified Vaccinia Ankara virus (MVA) as an initial screening system, and by validating identified hits in an MPXV cell culture system, thus leading into downstream lead candidate development (Rapid Synergy: Monkeypox, Emory SoM/WHSC I3 Award).

- Novel antivirals for Nipah Virus (NiV). We have been using our first-generation Nipah mini-genome replication system to screen a unique nucleoside analog library that our collaborators in the Schinazi lab have been building over the course of decades. By leveraging minigenome (MG) replicon-based approaches, we aim to identify compounds that demonstrate potent antiviral activity against NiV, which can serve as the basis for the development of novel antiviral therapies.

-Interactions of HIV with host factors-APOBEC3-HIV RT interactions. To block reverse transcription, cells express APOBEC3 (A3) family of restriction factors that suppress infection. Co-investigator Malim (King's college) has shown that HIV evades A3-mediated inhibition through the action of its Vif protein. While it has been established that A3s block HIV primarily through their cytidine deaminase activity, which causes hypermutation and genetic inactivation, they also inhibit RT itself (Nature Microbiol. Nov 20. 2017), through a mechanism that is poorly understood. As the co-Director of the HIV Interactions in Viral Evolution Center (HIVE) (http://hive.scripps.edu/index.html), a Center for AIDS molecular interactions and evolution studies, I am leading efforts to characterize the RT-A3 interactions (U54 GM103368).

-HIV eradication studies through novel techniques for visualization of viral RNA, DNA and protein. We recently published a novel microscopy-based method (MICDDRP or Multiplex Immunofluorescent Cell-based Detection of DNA, RNA and Protein) (Nature Commun. 8:1882. 2017) that should facilitate investigations on fundamental biology of HIV or other viruses, including the specific role of host factors on integration, transcription, and latency, and also provide critical advances in elucidating mechanisms of antiviral inhibition at the level of single cell, single viral genome, and single integration site.

-Novel antivirals targeting the RNase H activity of HIV (PLoS Pathogens 9: e1003125, 2013; J Med Chem. 60: 5045-5056, 2017) (with Z. Wang, and R. Ishima, Univ of Pittsburgh) (R01 AI100890 NCE).

-Novel antivirals for treatment of HBV infection. We are targeting HBV through the development and characterization of antivirals that block HBV by targeting its capsid, reverse transcriptase, or RNase H active sites (PLoS Pathog. 2013 Jan;9(1):e1003125; Antimicrob Agents Chemother. 61, e00245-17, 2017; Hepatology 62:1024-36, 2015; ). We are also developing cutting-edge microscopy-based and molecular biology based approaches to study HBV biology (R01 AI121315).

References
1: Puray-Chavez M, Tedbury PR, Huber AD, Ukah OB, Yapo V, Liu D, Ji J, Wolf JJ, Engelman AN, Sarafianos SG. Multiplex single-cell visualization of nucleic acids and protein during HIV infection. Nature Commun. 2017 Dec 1;8(1):1882. doi: 10.1038/s41467-017-01693-z. PubMed PMID: 29192235; PubMed Central PMCID: PMC5709414.

2: Gres AT, Kirby KA, KewalRamani VN, Tanner JJ, Pornillos O, Sarafianos SG. STRUCTURAL VIROLOGY. X-ray crystal structures of native HIV-1 capsid protein reveal conformational variability. Science. 2015 Jul 3;349(6243):99-103. doi: 10.1126/science.aaa5936. Epub 2015 Jun 4. PubMed PMID: 26044298; PubMed Central PMCID: PMC4584149.

3: Salie ZL, Kirby KA, Michailidis E, Marchand B, Singh K, Rohan LC, Kodama EN, Mitsuya H, Parniak MA, Sarafianos SG. Structural basis of HIV inhibition by translocation-defective RT inhibitor 4'-ethynyl-2-fluoro-2'-deoxyadenosine (EFdA). Proc Natl Acad Sci U S A. 2016 Aug 16;113(33):9274-9. doi: 10.1073/pnas.1605223113. Epub 2016 Aug 3. PubMed PMID: 27489345; PubMed Central PMCID: PMC4995989.

4: Lan S, Neilsen G, Slack RL, Cantara WA, Castaner AE, Lorson ZC, Lulkin N, Zhang H, Lee J, Cilento ME, Tedbury PR, Sarafianos SG. Nirmatrelvir Resistance in SARS-CoV-2 Omicron_BA.1 and WA1 Replicons and Escape Strategies. bioRxiv [Preprint]. 2023 Jan 3:2022.12.31.522389. doi: 10.1101/2022.12.31.522389. PMID: 36656782; PMCID: PMC9844013.

Atlanta Society of Mentors (ASOM), 2021

Diversity: Inclusion in the Modern Workplace, 2020

Unconscious Bias Training, 2023

Building Supportive Communities: Clery Act & Title IX, 2021

Preventing Harassment & Discrimination: Supervisors, 2023