Assessment of deoxyhypusine hydroxylase as a putative, novel drug target

B Kerscher, E Nzukou, A Kaiser

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

Antimalarial drug resistance has nowadays reached each drug class on the market for longer than 10 years. The focus on validated, classical targets has severe drawbacks. If resistance is arising or already present in the field, a target-based High-Throughput-Screening (HTS) with the respective target involves the risk of identifying compounds to which field populations are also resistant. Thus, it appears that a rewarding albeit demanding challenge for target-based drug discovery is to identify novel drug targets. In the search for new targets for antimalarials, we have investigated the biosynthesis of hypusine, present in eukaryotic initiation factor 5A (eIF5A). Deoxyhypusine hydroxylase (DOHH), which has recently been cloned and expressed from P. falciparum, completes the modification of eIF5A through hydroxylation. Here, we assess the present druggable data on Plasmodium DOHH and its human counterpart. Plasmodium DOHH arose from a cyanobacterial phycobilin lyase by loss of function. It has a low FASTA score of 27 to its human counterpart. The HEAT-like repeats present in the parasite DOHH differ in number and amino acid identity from its human ortholog and might be of considerable interest for inhibitor design.
Original languageEnglish
Pages (from-to)471-477
Number of pages7
JournalAmino Acids
Volume38
Issue number2
DOIs
Publication statusPublished - Feb 2010

Fingerprint

deoxyhypusine hydroxylase
Eukaryotic Initiation Factors
Plasmodium
Antimalarials
Pharmaceutical Preparations
Phycobilins
Hydroxylation
Lyases
Biosynthesis
Drug Discovery
Drug Resistance
Screening
Parasites
Throughput
Amino Acids

Keywords

  • deoxyhypusine hydroxylase
  • plasmodium
  • malaria
  • drug target

Cite this

Assessment of deoxyhypusine hydroxylase as a putative, novel drug target. / Kerscher, B; Nzukou, E; Kaiser, A.

In: Amino Acids, Vol. 38, No. 2, 02.2010, p. 471-477.

Research output: Contribution to journalArticle

Kerscher, B ; Nzukou, E ; Kaiser, A. / Assessment of deoxyhypusine hydroxylase as a putative, novel drug target. In: Amino Acids. 2010 ; Vol. 38, No. 2. pp. 471-477.
@article{d026e00bf0a74b8db1faf41890951a94,
title = "Assessment of deoxyhypusine hydroxylase as a putative, novel drug target",
abstract = "Antimalarial drug resistance has nowadays reached each drug class on the market for longer than 10 years. The focus on validated, classical targets has severe drawbacks. If resistance is arising or already present in the field, a target-based High-Throughput-Screening (HTS) with the respective target involves the risk of identifying compounds to which field populations are also resistant. Thus, it appears that a rewarding albeit demanding challenge for target-based drug discovery is to identify novel drug targets. In the search for new targets for antimalarials, we have investigated the biosynthesis of hypusine, present in eukaryotic initiation factor 5A (eIF5A). Deoxyhypusine hydroxylase (DOHH), which has recently been cloned and expressed from P. falciparum, completes the modification of eIF5A through hydroxylation. Here, we assess the present druggable data on Plasmodium DOHH and its human counterpart. Plasmodium DOHH arose from a cyanobacterial phycobilin lyase by loss of function. It has a low FASTA score of 27 to its human counterpart. The HEAT-like repeats present in the parasite DOHH differ in number and amino acid identity from its human ortholog and might be of considerable interest for inhibitor design.",
keywords = "deoxyhypusine hydroxylase , plasmodium, malaria, drug target",
author = "B Kerscher and E Nzukou and A Kaiser",
year = "2010",
month = "2",
doi = "10.1007/s00726-009-0406-9",
language = "English",
volume = "38",
pages = "471--477",
journal = "Amino Acids",
issn = "0939-4451",
publisher = "SPRINGER WIEN",
number = "2",

}

TY - JOUR

T1 - Assessment of deoxyhypusine hydroxylase as a putative, novel drug target

AU - Kerscher, B

AU - Nzukou, E

AU - Kaiser, A

PY - 2010/2

Y1 - 2010/2

N2 - Antimalarial drug resistance has nowadays reached each drug class on the market for longer than 10 years. The focus on validated, classical targets has severe drawbacks. If resistance is arising or already present in the field, a target-based High-Throughput-Screening (HTS) with the respective target involves the risk of identifying compounds to which field populations are also resistant. Thus, it appears that a rewarding albeit demanding challenge for target-based drug discovery is to identify novel drug targets. In the search for new targets for antimalarials, we have investigated the biosynthesis of hypusine, present in eukaryotic initiation factor 5A (eIF5A). Deoxyhypusine hydroxylase (DOHH), which has recently been cloned and expressed from P. falciparum, completes the modification of eIF5A through hydroxylation. Here, we assess the present druggable data on Plasmodium DOHH and its human counterpart. Plasmodium DOHH arose from a cyanobacterial phycobilin lyase by loss of function. It has a low FASTA score of 27 to its human counterpart. The HEAT-like repeats present in the parasite DOHH differ in number and amino acid identity from its human ortholog and might be of considerable interest for inhibitor design.

AB - Antimalarial drug resistance has nowadays reached each drug class on the market for longer than 10 years. The focus on validated, classical targets has severe drawbacks. If resistance is arising or already present in the field, a target-based High-Throughput-Screening (HTS) with the respective target involves the risk of identifying compounds to which field populations are also resistant. Thus, it appears that a rewarding albeit demanding challenge for target-based drug discovery is to identify novel drug targets. In the search for new targets for antimalarials, we have investigated the biosynthesis of hypusine, present in eukaryotic initiation factor 5A (eIF5A). Deoxyhypusine hydroxylase (DOHH), which has recently been cloned and expressed from P. falciparum, completes the modification of eIF5A through hydroxylation. Here, we assess the present druggable data on Plasmodium DOHH and its human counterpart. Plasmodium DOHH arose from a cyanobacterial phycobilin lyase by loss of function. It has a low FASTA score of 27 to its human counterpart. The HEAT-like repeats present in the parasite DOHH differ in number and amino acid identity from its human ortholog and might be of considerable interest for inhibitor design.

KW - deoxyhypusine hydroxylase

KW - plasmodium

KW - malaria

KW - drug target

U2 - 10.1007/s00726-009-0406-9

DO - 10.1007/s00726-009-0406-9

M3 - Article

VL - 38

SP - 471

EP - 477

JO - Amino Acids

JF - Amino Acids

SN - 0939-4451

IS - 2

ER -