Adapting pharmacokinetic properties of a humanized anti-interleukin-8 antibody for therapeutic applications using site-specific pegylation.

A neutralizing anti-interleukin-(IL-)8 monoclonal antibody was humanized by grafting the complementary determining regions onto the human IgG framework. Subsequent alanine scanning mutagenesis and phage display enabled the production of an affinity matured antibody with a >100-fold improvement in IL-8 binding. Antibody fragments can be efficiently produced in Escherichia coli but have the limitation of rapid clearance rates in vivo.

An investigation of angiotensin II agonist and antagonist analogues with 5,5-dimethylthiazolidine-4-carboxylic acid and other constrained amino acids.

To probe the receptor-bound conformational requirements of angiotensin II (ANG II) octapeptide agonists and antagonists, the synthesis and biological activities of [Sar1]ANG II agonist and [Sar1,X8]ANG II antagonist analogues (X8 = Ile, D-Phe, or Aib) bearing conformational constraints in positions 3, 5, and 7 were investigated and compared with previous literature efforts. The conformational constraints that were examined include Pro, Dtc (5,5-dimethylthiazolidine-4-carboxylic acid), Aib, Cle, (NMe)Ala, (NMe)Ile, and the lactam modification, L,L-lactam-Phe, previously described by Freidinger et al. (J.

Epitopes of human immunodeficiency virus type 1 (HIV-1) envelope glycoproteins recognized by antibodies in the sera of HIV-1-infected individuals.

Sera from human immunodeficiency virus (HIV)-infected study subjects and controls were analyzed by enzyme-linked immunosorbent assay using 10 synthetic peptides to identify epitopes of HIV envelope glycoproteins (ENVgp) that were recognized by antibodies. Two epitopes of HIV ENVgp, ENVP466 (amino acids 466-481) and ENVP497 (amino acids 497-509), were recognized by antibodies in the sera of most HIV-infected individuals. The frequency of individuals with detectable serum antibodies to these two epitopes was not associated with the stage of HIV disease.

The role of position 4 in angiotensin II antagonism: a structure-activity study.

A number of [Sar1,(pX)Phe4]-ANG II and [Sar1,(pX)Phe4,Ile8]-ANG II analogues were prepared. A good correlation between pX structure in [Sar1,(pX)Phe4]-ANG II and antagonist activity could not be found. However, the data suggest a general trend: Position 4 para substituents that are hydrophilic and capable of donating a hydrogen atom in a hydrogen bond promote agonist activity, while para substituents that are hydrophobic and incapable of donating a hydrogen atom promote antagonist activity.

Potent angiotensin II antagonists with non-beta-branched amino acids in position 5.

Amino acids with lipophilic side chains that contain more than one functional group on the beta-carbon, i.e. a beta-branched hydrocarbon moiety, are required in position 5 of angiotensin II (AII) analogue with potent agonist activity.

The importance of residues 2 (arginine) and 6 (histidine) in high-affinity angiotensin II antagonists.

The structure-antagonist activity relationship is described for analogues of [Sar1,Ile8]angiotensin II substituted in position 2 (arginine) and position 6 (histidine). An extreme sensitivity of potency to alterations in these positions was observed, suggesting that both residues are important for binding. Evidence is presented suggesting that the position 6 histidine side chain in angiotensin II (AII) is not involved in receptor stimulation.

Effects of D-amino acid substitution on antagonist activities of angiotensin II analogues.

The synthesis and biological activities of angiotensin II (AII) analogues are described and compared to the literature. D-Amino acid substitution was employed to search for novel AII antagonists that would also display reduced partial agonist activity. Substitution of D-amino acids into the interior positions 2-7 of [Sar1,Ile8]-AII gave rise to inactive compounds or weak antagonists.