8QKJ

PvSub1 Catalytic Domain in Complex with Peptidomimetic Inhibitor (MAM-133)

Summary for 8QKJ

• Entry DOI: 10.2210/pdb8qkj/pdb
• Related: 8QKG
• Descriptor: subtilisin, Peptidomimetic Inhibitor (MAM-133), CALCIUM ION, ... (6 entities in total)
• Functional Keywords: subtilisin, alpha-ketoamides, sar, hydrolase
• Biological source: Plasmodium vivax (malaria parasite P. vivax); More
• Total number of polymer chains: 4
• Total formula weight: 141601.87

Authors

Batista, F.A.,Martinez, M.,Bouillon, A.,Mechaly, A.,Alzari, P.M.,Haouz, A.,Barale, J.C. (deposition date: 2023-09-15, release date: 2024-03-20, Last modification date: 2024-05-01)

Primary citation

Legru, A.,Batista, F.A.,Puszko, A.K.,Bouillon, A.,Maurel, M.,Martinez, M.,Ejjoummany, A.,Ortega Varga, L.,Adler, P.,Mechaly, A.,Hadjadj, M.,Sosnowski, P.,Hopfgartner, G.,Alzari, P.M.,Blondel, A.,Haouz, A.,Barale, J.C.,Hernandez, J.F.
Insights from structure-activity relationships and the binding mode of peptidic alpha-ketoamide inhibitors of the malaria drug target subtilisin-like SUB1.
Eur.J.Med.Chem., 269:116308-116308, 2024

PubMed Abstract: Plasmodium multi-resistance, including against artemisinin, seriously threatens malaria treatment and control. Hence, new drugs are urgently needed, ideally targeting different parasitic stages, which are not yet targeted by current drugs. The SUB1 protease is involved in both hepatic and blood stages due to its essential role in the egress of parasites from host cells, and, as potential new target, it would meet the above criteria. We report here the synthesis as well as the biological and structural evaluation of substrate-based α-ketoamide SUB1 pseudopeptidic inhibitors encompassing positions P4-P2'. By individually substituting each position of the reference compound 1 (MAM-117, Ac-Ile-Thr-Ala-AlaCO-Asp-Glu (Oall)-NH), we better characterized the structural determinants for SUB1 binding. We first identified compound 8 with IC values of 50 and 570 nM against Pv- and PfSUB1, respectively (about 3.5-fold higher potency compared to 1). Compound 8 inhibited P. falciparum merozoite egress in culture by 37% at 100 μM. By increasing the overall hydrophobicity of the compounds, we could improve the PfSUB1 inhibition level and antiparasitic activity, as shown with compound 40 (IC values of 12 and 10 nM against Pv- and PfSUB1, respectively, IC value of 23 μM on P. falciparum merozoite egress). We also found that 8 was highly selective towards SUB1 over three mammalian serine peptidases, supporting the promising value of this compound. Finally, several crystal 3D-structures of SUB1-inhibitor complexes, including with 8, were solved at high resolution to decipher the binding mode of these compounds.

PubMed: 38503166
DOI: 10.1016/j.ejmech.2024.116308

Experimental method

X-RAY DIFFRACTION (1.767 Å)