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  • br Experimental section br Abbreviations PSA puromycin sensi

    2022-11-18


    Experimental section
    Abbreviations PSA, puromycin–sensitive aminopeptidase; APN, aminopeptidase N; AML, acute myeloid Leukemia; ALL, acute lymphoblastic leukemia; AADR, amino BMS 309403 mg deprivation response; PAN, puromycin aminonucleoside; DCC, dicyclohexyl carbodiimide; NHS, N–hydroxy succinimide; TFA, trifluoroacetic acid; Ala–4–MNA, alanine–4–methoxy–2–naphthylamide; Ala–AMC, alanine–7–amino–4–methylcoumarin; MTT, 3–(4,5–dimethylthiazol–2–yl)–2,5–diphenyl tetrazolium bromide; TLC, thin layer chromatography.
    Associated content
    Author contributions
    Funding sources This research was supported by the funds from the Center for Drug Design at the University of Minnesota.
    Acknowledgment This research was supported by the funds from the Center for Drug Design at the University of Minnesota.
    Introduction Protozoan dimorphic parasites of genus Leishmania cause leishmaniasis which is characterized by a wide spectrum of clinical manifestations that includes ulcerative skin lesions to life-threatening visceral infections. Leishmania parasites are transmitted through the bite of sandfly to the mammalian hosts [1]. Approximately 12 million people are affected by leishmaniasis in 80 countries with about 400,000 new cases reported each year [2]. There are estimates of about 70,000 deaths occurring annually and a further 350 million at risk of getting infected [3]. Due to the unavailability of any significant vaccination, chemotherapy along with vector control continue to remain a significant element in the control of all forms of leishmaniasis. The prominent antileishmanials used currently include pentavalent antimony, amphotericin B and miltefosine. Even though effective, the current line of antileishmanials are toxic, unaffordable and carry a risk of turning ineffective due to the emergence of drug resistant parasites [4,5]. This highlights the need BMS 309403 mg to design and develop new drugs against leishmaniasis. Aminopeptidases are exopeptidases catalyzing the cleavage of amino acids from N-terminal in proteins and peptides [6]. The metal dependent aminopeptidase-catalyzed degradation of smaller peptides in the terminal stages of protein degradation pathway provides free amino acids to the organism [7,8]. The genome of L. donovani encodes at least twelve aminopeptidases most of which belong to the M1, M20, M18, M17 and M24 aminopeptidases. There are several reports of these proteins to be druggable targets against many adversaries like cancer and malaria [9,10]. Methionine aminopeptidases (MAPs) are ubiquitous and highly conserved metal dependent hydrolases that remove N-terminal initiator methionine from nascent polypeptides either co-translationally or post-translationally [11] and belong to the M24 class of peptidases as per the MEROPS peptidase database classification (https://merops.sanger.ac.uk/). The excision of initiator methionine amino acid residue is a prerequisite for further post-translational modifications of nascent polypeptides viz. myristoylation, localization, proper folding, and protein activity in both prokaryotes and eukaryotes [[12], [13], [14]]. To hydrolyze the methionyl amino acid residue in the ultimate position, MAPs require a small uncharged residue (usually Gly or Ala) at the penultimate position of the nascent polypeptide chain [15]. MAPs are grouped into two categories: type I (MAP1) and type II (MAP2), with the unique insertion of nearly 60 amino acids residues in MAP2 at the C-terminus of the catalytic domain [16]. While as, the MAPs of prokaryotic bacteria and archaea contain the minimal catalytic domain, MAPs of eukaryotes possess additional N-terminal domains [17] viz. the occurrence of N-terminal zinc-finger motif (like in human or yeast MAPs) or the existence of a polybasic/polyacidic domain like the one reported for human MAP type IIb that is responsible for the phosphorylation blockade of eukaryotic initiation factor 2a subunit [18]. Notably, eukaryotes harbour both isoforms unlike prokaryotic genomes that encode only one isoform: type I in bacteria and type II in archaea [19]. A previous report on the abundance of two isoforms in eukaryotes suggests MAP1 to be constitutively expressed and is thence considered as a house-keeping enzyme. On the contrary, MAP2 expression is regulated by extra-cellular signals and cell cycle status [20].