View source for 8uac


==CATHEPSIN L IN COMPLEX WITH AC1115==
<StructureSection load='8uac' size='340' side='right'caption='[[8uac]], [[Resolution|resolution]] 1.40&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[8uac]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=8UAC OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8UAC FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.4&#8491;</td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=8uac FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8uac OCA], [https://pdbe.org/8uac PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8uac RCSB], [https://www.ebi.ac.uk/pdbsum/8uac PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8uac ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/CATL1_HUMAN CATL1_HUMAN] Important for the overall degradation of proteins in lysosomes.
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
BACKGROUND: Oral antiviral drugs with improved antiviral potency and safety are needed to address current challenges in clinical practice for treatment of COVID-19, including the risks of rebound, drug-drug interactions, and emerging resistance. METHODS: Olgotrelvir (STI-1558) is designed as a next-generation antiviral targeting the SARS-CoV-2 main protease (M(pro)), an essential enzyme for SARS-CoV-2 replication, and human cathepsin L (CTSL), a key enzyme for SARS-CoV-2 entry into host cells. FINDINGS: Olgotrelvir is a highly bioavailable oral prodrug that is converted in plasma to its active form, AC1115. The dual mechanism of action of olgotrelvir and AC1115 was confirmed by enzyme activity inhibition assays and co-crystal structures of AC1115 with SARS-CoV-2 M(pro) and human CTSL. AC1115 displayed antiviral activity by inhibiting replication of all tested SARS-CoV-2 variants in cell culture systems. Olgotrelvir also inhibited viral entry into cells using SARS-CoV-2 Spike-mediated pseudotypes by inhibition of host CTSL. In the K18-hACE2 transgenic mouse model of SARS-CoV-2-mediated disease, olgotrelvir significantly reduced the virus load in the lungs, prevented body weight loss, and reduced cytokine release and lung pathologies. Olgotrelvir demonstrated potent activity against the nirmatrelvir-resistant M(pro) E166 mutants. Olgotrelvir showed enhanced oral bioavailability in animal models and in humans with significant plasma exposure without ritonavir. In phase I studies (ClinicalTrials.gov: NCT05364840 and NCT05523739), olgotrelvir demonstrated a favorable safety profile and antiviral activity. CONCLUSIONS: Olgotrelvir is an oral inhibitor targeting M(pro) and CTSL with high antiviral activity and plasma exposure and is a standalone treatment candidate for COVID-19. FUNDING: Funded by Sorrento Therapeutics.

Olgotrelvir, a dual inhibitor of SARS-CoV-2 M(pro) and cathepsin L, as a standalone antiviral oral intervention candidate for COVID-19.,Mao L, Shaabani N, Zhang X, Jin C, Xu W, Argent C, Kushnareva Y, Powers C, Stegman K, Liu J, Xie H, Xu C, Bao Y, Xu L, Zhang Y, Yang H, Qian S, Hu Y, Shao J, Zhang C, Li T, Li Y, Liu N, Lin Z, Wang S, Wang C, Shen W, Lin Y, Shu D, Zhu Z, Kotoi O, Kerwin L, Han Q, Chumakova L, Teijaro J, Royal M, Brunswick M, Allen R, Ji H, Lu H, Xu X Med. 2024 Jan 12;5(1):42-61.e23. doi: 10.1016/j.medj.2023.12.004. Epub 2024 Jan , 4. PMID:38181791<ref>PMID:38181791</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 8uac" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Chao A]]
[[Category: DuPrez KT]]
[[Category: Han FQ]]