Viral Proteases (HIV-1/HTLV-1, HCV, Dengue/Zika)

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Rationale

Viral proteases are proven drug targets against a multitude of disease-causing human-infecting viruses, particularly and historically starting with Human Immunodeficiency Virus 1 (HIV-1). Structure-based design strategies combined with the understanding of fundamental resistance mechanisms in HIV-1 protease offer critical lessons that can be applied to the proteases of other viruses as we work towards developing novel antiviral drugs. 

What we're doing

We have investigated the molecular interactions underlying substrate binding and drug resistance in HIV-1 and Hepatitis C Virus (HCV) proteases, and how chemical modifications of the inhibitor can counter resistance. The strategies developed from these systems inform the design of inhibitors against proteases of viruses where no antiviral drug exists. Our current efforts focus on developing potent antivirals against Human T-Lymphotrophic Virus 1 (HTLV-1) protease.

Publication Highlights

Matthew AN, Zephyr J, Rao DN, Henes M, Kamran W, Kosovrasti K, Hedger AK, Lockbaum GJ, Timm J, Ali A, Kurt Yilmaz N*, Schiffer CA “Avoiding Drug Resistance by Substrate Envelope Guided Design: Toward Potent and Robust HCV NS3/4A Protease Inhibitors” mBio, Vol.11, Iss. 2, e00172-20 (2020). (*joint corresponding author)

Lockbaum GJ, Henes M, Talledge N, Rusere LN, Kosovrasti K, Nalivaika EA, Somasundaran M, Ali A, Mansky LM, Kurt Yilmaz N, Schiffer CA. “Inhibiting HTLV-1 Protease: A Viable Antiviral Target” ACS Chemical Biology, Vol. 16, Iss. 3, pp. 529-538 (2021).

Ozen, A.*; Lin, K.-H.*; Kurt Yilmaz, N.*,#; Schiffer, C.A.# “Structural Basis and Distal Effects of Gag Substrate Coevolution in Drug Resistance to HIV-1 Protease”, Proc. Natl. Acad. Sci. USA, Vol. 111, Iss. 45, 15993-15998 (2014). (*joint first author) (#corresponding author).

Khan, S.N.; Persons, J.D.; Paulsen, J.L.; Guerrero, M.; Schiffer, C.A.; Kurt Yilmaz, N.*; Ishima, R.* “Probing Structural Changes among Analogous Inhibitor-Bound Forms of HIV‐1 Protease and a Drug-Resistant Mutant in Solution by Nuclear Magnetic Resonance” Biochemistry, Vol. 57, Iss. 10, pp. 1652-1662 (2018). (*joint corresponding author)

Henes M, Lockbaum GJ, Kosovrasti K, Leidner F, Nachum GS, Nalivaika EA, Lee S-K, Spielvogel E, Zhou S, Swanstrom R, Bolon DNA, Kurt Yilmaz N*, Schiffer CA. “Picomolar to Micromolar: Elucidating the Role of Distal Mutations in HIV-1 Protease in Conferring Drug Resistance” ACS Chemical Biology, Vol. 14, Iss. 11, pp. 2441-2452 (2019). (*joint corresponding author)