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Present study manifested the crucial role of ATG8 protein as a potential target in combating <jats:italic>L. major<\/jats:italic> infection. Using machine learning algorithms, we identified non\u2010conserved motifs within the ATG8 in <jats:italic>L. major<\/jats:italic>. Subsequently, a peptide library was generated based on these motifs, and three peptides were selected for further investigation through molecular docking and molecular dynamics simulations. Surface Plasmon Resonance (SPR) experiments confirmed the direct interaction between ATG8 and the identified peptides. Remarkably, these peptides demonstrated the ability to cross the parasite membrane and exert profound effects on <jats:italic>L. major<\/jats:italic>. Peptide treatment significantly impacted parasite survival, inducing alterations in the cell cycle and morphology. Furthermore, the peptides were found to modulate autophagosome formation, particularly under starved conditions, indicating their involvement in autophagy regulation within <jats:italic>L. major. In vitro<\/jats:italic> studies revealed that the selected peptides effectively decreased the parasite load within the infected host cells. Encouragingly, <jats:italic>in\u2005vivo<\/jats:italic> experiments corroborated these findings, demonstrating a reduction in parasite burden upon peptide administration. Additionally, the peptides were observed to affect the levels of LC3II, a known autophagy marker within the host cells. Collectively, our findings highlight the efficacy of these novel peptides in targeting <jats:italic>L. major<\/jats:italic> ATG8 and disrupting parasite survival, wherein P2 is showing prominent effect on <jats:italic>L. major<\/jats:italic> as compared to P1. These results provide valuable insights into the development of innovative therapeutic strategies against leishmaniasis.<\/jats:p>","DOI":"10.1002\/cmdc.202300679","type":"journal-article","created":{"date-parts":[[2024,2,7]],"date-time":"2024-02-07T05:06:08Z","timestamp":1707282368000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Targeting peptide based therapeutics: Integrated computational and experimental studies of autophagic regulation in host\u2010parasite interaction"],"prefix":"10.1002","volume":"19","author":[{"given":"Vrushali","family":"Guhe","sequence":"first","affiliation":[{"name":"Systems Medicine Lab National Centre for Cell Science, NCCS Complex, Ganeshkhind, SP Pune University Campus  Pune 411007 India Phone"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3817-8819","authenticated-orcid":false,"given":"Shailza","family":"Singh","sequence":"additional","affiliation":[{"name":"Systems Medicine Lab National Centre for Cell Science, NCCS Complex, Ganeshkhind, SP Pune University Campus  Pune 411007 India Phone"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2024,2,22]]},"reference":[{"key":"e_1_2_10_1_1","first-page":"1","volume":"6","author":"Arenas R.","year":"2017","journal-title":"F1000Research"},{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.21037\/tlcr-22-192"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1111\/ced.14919"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2014.00193"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1039\/C5RA02669E"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.3389\/fchem.2017.00005"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.3389\/fcimb.2020.00105"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.3389\/fcimb.2016.00194"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1093\/database\/bau051"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.resmic.2011.02.005"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms22094400"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41419-019-2038-7"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF03402040"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M706214200"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-313X.2010.04166.x"},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2019.02523"},{"key":"e_1_2_10_17_1","doi-asserted-by":"publisher","DOI":"10.3390\/molecules27103142"},{"key":"e_1_2_10_18_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2958.2006.05274.x"},{"key":"e_1_2_10_19_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1008455"},{"key":"e_1_2_10_20_1","doi-asserted-by":"publisher","DOI":"10.4161\/auto.5.2.7328"},{"key":"e_1_2_10_21_1","volume":"8","author":"Williams R. 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