{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,17]],"date-time":"2026-06-17T01:12:43Z","timestamp":1781658763154,"version":"3.54.5"},"reference-count":0,"publisher":"Portland Press Ltd.","license":[{"start":{"date-parts":[[2020,3,23]],"date-time":"2020-03-23T00:00:00Z","timestamp":1584921600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/2.0\/"}],"content-domain":{"domain":["portlandpress.com"],"crossmark-restriction":true},"short-container-title":[],"abstract":"<jats:p>Metacaspases are novel cysteine proteases found in apicomplexan whose function is poorly understood. Our earlier studies on Plasmodium falciparum metacaspase-2 (PfMCA-2) revealed that the caspase inhibitor, Z-FA-FMK efficiently inhibited PfMCA-2 activity and, expression, and significantly blocked in vitro progression of the parasite developmental cycle via apoptosis-like parasite death. Building on these findings, we synthesized a set of novel inhibitors based on structural modification of Z-FA-FMK with the amides of piperic acid and investigated their effect on PfMCA-2. One of these analogues, SS-5, specifically inhibited the activity and expression of PfMCA-2. The activities of some other known malarial proteases (falcipains, plasmepsins, &amp; vivapain), and human cathepsins-B, D and L, and caspase-3 and -7 were not inhibited by SS-5.\u00a0SS-5 blocked the development of P. falciparumin vitro (IC50 1\u00b5M) and caused prominent morphological distortions. Incubation with SS-5 led to persistent parasite oxidative stress accompanied by depolarization of mitochondrial potential and accumulation of intracellular Ca2+. SS-5 also inhibited the development of P. berghei in a murine model. Our results suggest that the inhibition of PfMCA-2 results in oxidative stress, leading to apoptosis-like parasite death. Thus, SS-5 offers a starting point for optimization of new antimalarials, and PfMCA-2 could be a novel target for antimalarial drug discovery.<\/jats:p>","DOI":"10.1042\/bcj20200050","type":"journal-article","created":{"date-parts":[[2020,3,23]],"date-time":"2020-03-23T12:40:39Z","timestamp":1584967239000},"update-policy":"https:\/\/doi.org\/10.1042\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["A Nonpeptidyl Molecule Modulates Apoptosis-like Cell Death by Inhibiting P.falciparum Metacapase-2"],"prefix":"10.1042","author":[{"given":"Vandana","family":"Kumari","sequence":"first","affiliation":[{"name":"NIMR, Delhi, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sudha","family":"Sankar","sequence":"first","affiliation":[{"name":"IIIM, Jammu and Kashmir, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kona Madhavinadha","family":"Prasad","sequence":"first","affiliation":[{"name":"NIMR, Delhi, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohammad","family":"Kashif","sequence":"first","affiliation":[{"name":"NII, Delhi, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Inderjeet","family":"Kalia","sequence":"first","affiliation":[{"name":"NII, Delhi, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rajkishor","family":"Rai","sequence":"first","affiliation":[{"name":"IIIM, Delhi, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Agam P","family":"Singh","sequence":"first","affiliation":[{"name":"NII, Delhi, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kailash Chand","family":"Pandey","sequence":"first","affiliation":[{"name":"National Institute of Malaria Research, Delhi, India"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"288","published-online":{"date-parts":[[2020,3,23]]},"container-title":["Biochemical Journal"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/portlandpress.com\/biochemj\/article-pdf\/doi\/10.1042\/BCJ20200050\/870064\/bcj-2020-0050.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"http:\/\/portlandpress.com\/biochemj\/article-pdf\/doi\/10.1042\/BCJ20200050\/870064\/bcj-2020-0050.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2020,3,23]],"date-time":"2020-03-23T12:40:40Z","timestamp":1584967240000},"score":1,"resource":{"primary":{"URL":"https:\/\/portlandpress.com\/biochemj\/article\/doi\/10.1042\/BCJ20200050\/222446\/A-Nonpeptidyl-Molecule-Modulates-Apoptosislike"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,3,23]]},"references-count":0,"URL":"https:\/\/doi.org\/10.1042\/bcj20200050","relation":{},"ISSN":["0264-6021","1470-8728"],"issn-type":[{"value":"0264-6021","type":"print"},{"value":"1470-8728","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,3,23]]},"article-number":"BCJ20200050"}}