Pepstatin A (Synonyms: NSC 272671, Pepsin Inhibitor S 735A)

Pepstatin A is an orally active inhibitor of aspartic proteases, which is produced by actinomycetes. It exhibits inhibitory activity with IC₅₀ values of 4.5 nM, 6.2 nM, 150 nM, 290 nM, 520 nM, and 260 nM against hemoglobin-pepsin, hemoglobin-proctase, casein-pepsin, casein-proctase, casein-acid protease, and hemoglobin-acid protease, respectively. Additionally, pepstatin has been found to inhibit HIV protease ^[1-3].

Pepstatin A(0-120 µM) suppressed receptor activator of NF-κB ligand (RANKL)-induced osteoclast differentiation^[4]. Pepstatin A(0.1-0.3 µM) caused a reproducible, concentration-related increase in the extracellular acidification rate in two microglial cell lines, Ra2 and 6-3^[5]. Pepstatin A significantly hindered influenza virus replication, probably by modulating host cell autophagic/apoptotic responses^[6].

Pepstatin (0.5-50 mg/kg; p.o.) suppresses stomach ulceration of the pylorus in ligated Shay rats^[1].

References:
[1]. Yoshida H, Okamoto K, et,al. Pepstatin A, an aspartic proteinase inhibitor, suppresses RANKL-induced osteoclast differentiation. J Biochem. 2006 Mar;139(3):583-90. doi: 10.1093/jb/mvj066. PMID: 16567424.
[2]. Seelmeier S, Schmidt H, et,al. Human immunodeficiency virus has an aspartic-type protease that can be inhibited by pepstatin A. Proc Natl Acad Sci U S A. 1988 Sep;85(18):6612-6. doi: 10.1073/pnas.85.18.6612. PMID: 3045820; PMCID: PMC282027.
[3]. Seelmeier S, Schmidt H, et,al. Human immunodeficiency virus has an aspartic-type protease that can be inhibited by pepstatin A. Proc Natl Acad Sci U S A. 1988 Sep;85(18):6612-6. doi: 10.1073/pnas.85.18.6612. PMID: 3045820; PMCID: PMC282027.
[4]. Yoshida H, Okamoto K, et,al.Pepstatin A, an aspartic proteinase inhibitor, suppresses RANKL-induced osteoclast differentiation. J Biochem. 2006 Mar;139(3):583-90. doi: 10.1093/jb/mvj066. PMID: 16567424.
[5]. Okada M, Irie S, S et,al. Pepstatin A induces extracellular acidification distinct from aspartic protease inhibition in microglial cell lines. Glia. 2003 Aug;43(2):167-74. doi: 10.1002/glia.10237. PMID: 12838508.
[6]. Matarrese P, Nencioni L, et,al. Pepstatin A alters host cell autophagic machinery and leads to a decrease in influenza A virus production. J Cell Physiol. 2011 Dec;226(12):3368-77. doi: 10.1002/jcp.22696. PMID: 21344392.