Linked Life Data

9371337

Source:http://linkedlifedata.com/resource/pubmed/id/9371337

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
11
pubmed:dateCreated
1998-1-23
pubmed:abstractText
Resistant virus was isolated from virus propagated in cell culture in the presence of the human immunodeficiency virus type 1 (HIV-1) proteinase inhibitor DMP 323, Ro 31-8959, or A-75925. The proteinase gene of resistant virus was sequenced, and key mutations (G48V, V82A, I84V, L90M, and G48V/L90M) were introduced into clones used for the expression, purification, and further characterization of the enzyme. The mutant enzymes were all less active than the wild-type enzyme, as judged by k(cat) and k(cat)/Km values. L90M had a lower Km than the wild type, whereas the G48V/L90M double mutant had an increased Km compared with that of the wild type, contributing to a 10-fold reduction in the k(cat)/Km. Vitality values were used to show that the enzyme of the I84V mutant is the enzyme most resistant to the two cyclic urea inhibitors DMP 323 and AHA 008. Virus with the same mutation is also resistant, although the double mutation L10F/I84V confers even greater resistance. All of these mutants are more resistant to DMP 323 than to AHA 008. The resistance of the I84V mutant may be attributed to a loss of van der Waals interactions with the inhibitor, since the larger amino acid side chain involved in the interaction is replaced by a smaller side chain. This is supported by the lower level of resistance to AHA 008 that was observed. The phenyl groups of AHA 008 should protrude deeper into the S1 and S1' subsites than those of the smaller compound DMP 323, reducing the loss of interaction energy. These results reveal that small structural modifications of inhibitors that do not affect the inhibitory effect on wild-type virus can influence the inhibition of resistant strains. This is of importance for optimizing drugs with respect to their potency and resistance.
pubmed:commentsCorrections
http://linkedlifedata.com/resource/pubmed/commentcorrection/9371337-1810306, http://linkedlifedata.com/resource/pubmed/commentcorrection/9371337-2062837, http://linkedlifedata.com/resource/pubmed/commentcorrection/9371337-2213822, http://linkedlifedata.com/resource/pubmed/commentcorrection/9371337-2469601, http://linkedlifedata.com/resource/pubmed/commentcorrection/9371337-2495366, http://linkedlifedata.com/resource/pubmed/commentcorrection/9371337-3290901, http://linkedlifedata.com/resource/pubmed/commentcorrection/9371337-7486905, http://linkedlifedata.com/resource/pubmed/commentcorrection/9371337-7626598, http://linkedlifedata.com/resource/pubmed/commentcorrection/9371337-7636988, http://linkedlifedata.com/resource/pubmed/commentcorrection/9371337-7700387, http://linkedlifedata.com/resource/pubmed/commentcorrection/9371337-7824947, http://linkedlifedata.com/resource/pubmed/commentcorrection/9371337-7827064, http://linkedlifedata.com/resource/pubmed/commentcorrection/9371337-8278812, http://linkedlifedata.com/resource/pubmed/commentcorrection/9371337-8648711, http://linkedlifedata.com/resource/pubmed/commentcorrection/9371337-8775804, http://linkedlifedata.com/resource/pubmed/commentcorrection/9371337-8807858, http://linkedlifedata.com/resource/pubmed/commentcorrection/9371337-8990341, http://linkedlifedata.com/resource/pubmed/commentcorrection/9371337-9083477
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Nov
pubmed:issn
0066-4804
pubmed:author
pubmed:issnType
Print
pubmed:volume
41
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
2383-8
pubmed:dateRevised
2009-11-18
pubmed:meshHeading
pubmed:year
1997
pubmed:articleTitle
Human immunodeficiency virus type 1 proteinase resistance to symmetric cyclic urea inhibitor analogs.
pubmed:affiliation
Department of Biochemistry, Uppsala University, Sweden.
pubmed:publicationType
Journal Article, Comparative Study, Research Support, Non-U.S. Gov't