Small dipeptide-based HIV protease inhibitors containing the hydroxymethylcarbonyl isostere as an ideal transition-state mimic.

@article{Kiso1999SmallDH,
  title={Small dipeptide-based HIV protease inhibitors containing the hydroxymethylcarbonyl isostere as an ideal transition-state mimic.},
  author={Yoshiaki Kiso and Hikaru Matsumoto and Shinsuke Mizumoto and T. Kimura and Yoichi Fujiwara and Kenichi Akaji},
  journal={Biopolymers},
  year={1999},
  volume={51 1},
  pages={
          59-68
        }
}
The human immunodeficiency virus (HIV) codes for an aspartic protease known to be essential for retroviral maturation and replication. HIV protease is formed from two identical 99 amino acid peptides. We synthesized [(NHCH2CH2-S-CH2CO)51-52, Ala67,95]HIV-1 protease using the thioether chemical ligation method, and then prepared the [(NHCH2CH2-S-CH2CO)51-52, Ala67,95, Cys98]HIV-1 protease dimer analogue covalently linked by a disulfide bridge. These HIV-1 protease analogues effectively cleaved… 
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41 Citations

Prodrug Forms of Peptidomimetic HIV Protease Inhibitors Using Intramolecular Cyclization Reaction
TLDR
In order to enhance the anti-HIV activity and improve the physicochemical characteristics, the designed and synthesized prodrug forms of a peptidomimetic HIV protease inhibitor, KNI-727, conjugated with a nucleoside reverse transcriptase inhibitors, AZT.
Design of inhibitors against HIV, HTLV-I, and Plasmodium falciparum aspartic proteases
TLDR
A novel class of aspartic protease inhibitors containing the hydroxymethylcarbonyl (HMC) isostere is designed and synthesized using an unnatural amino acid incorporated at the P1 site in a series of peptidomimetic compounds that mimic the natural substrates of the HIV, HTLV-I, and malarial as partic proteases.
Water-soluble prodrugs of dipeptide HIV protease inhibitors based on O-->N intramolecular acyl migration: Design, synthesis and kinetic study.
Combination of non-natural D-amino acid derivatives and allophenylnorstatine-dimethylthioproline scaffold in HIV protease inhibitors have high efficacy in mutant HIV.
TLDR
Interestingly, anti-HIV activity of all the D-amino acid-introduced inhibitors was remarkably enhanced in their anti-hIV activities against a Nelfinavir-resistant clone, which has a D30N mutation in the protease, over that of the wild-type strain.
Design and synthesis of broad-based mono- and bi- cyclic inhibitors of FIV and HIV proteases.
Design, synthesis, and biological evaluation of HIV/FIV protease inhibitors incorporating a conformationally constrained macrocycle with a small P3' residue.
Chapter 24. Pharmacokinetics and design of aspartyl protease inhibitors
Synthesis and biological evaluation of prodrug-type anti-HIV agents: ester conjugates of carboxylic acid-containing dipeptide HIV protease inhibitors and a reverse transcriptase inhibitor.
'Double-Drugs'--a new class of prodrug form of an HIV protease inhibitor conjugated with a reverse transcriptase inhibitor by a spontaneously cleavable linker.
Structure of HIV-1 protease in complex with potent inhibitor KNI-272 determined by high-resolution X-ray and neutron crystallography
TLDR
The results provide direct experimental evidence for proposed aspects of the catalytic mechanism of HIV-1 protease and can contribute substantially to the development of specific inhibitors for therapeutic application.
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References

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    Biopolymers
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The human immunodeficiency (HIV) codes for an aspartic protease known to be essential for retroviral maturation and replication. The HIV protease can recognize Phe-Pro and Tyr-Pro sequences as the…
DESIGN AND SYNTHESIS OF A COVALENTLY LINKED HIV-1 PROTEASE DIMER ANALOG AND PEPTIDOMIMETIC INHIBITORS
TLDR
This study suggests that the small-sized dipeptide HIV protease inhibitor, KNI-764, is a good candidate for anti-HIV drugs.
Structure of HIV-1 protease with KNI-272, a tight-binding transition-state analog containing allophenylnorstatine.
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Rational design and synthesis of a novel class of active site-targeted HIV protease inhibitors containing a hydroxymethylcarbonyl isostere. Use of phenylnorstatine or allophenylnorstatine as a transition-state mimic.
TLDR
A novel class of HIV-1 protease inhibitors containing a hydroxymethylcarbonyl (HMC) isostere were designed from the substrate transition state and synthesized, and incorporation of Pns-Pro or Apns- pro at the P1-P1' site gave potent and specific HIV- 1 prote enzyme inhibitors.
Conserved folding in retroviral proteases: crystal structure of a synthetic HIV-1 protease.
TLDR
The crystal structure of chemically synthesized HIV-1 protease has been determined with the use of a model based on the Rous sarcoma virus protease structure, and the observed arrangement of the dimer interface suggests possible designs for dimerization inhibitors.
KNI-102, a novel tripeptide HIV protease inhibitor containing allophenylnorstatine as a transition-state mimic.
TLDR
Z-Asn-Apns-Pro-NHBut (KNI-102) is the only tripeptide exhibiting substantial anti-HIV activity and may be of minimum size for potent, selective inhibition of HIV protease.
KNI‐577, a Potent Small‐Sized HIV Protease Inhibitor Based on the Dipeptide Containing the Hydroxymethylcarbonyl Isostere as an Ideal Transition‐State Mimic
TLDR
A novel class of HIV protease inhibitors containing allophenylnorstatine with a hydroxymethylcarbonyl (HMC) isostere is designed and synthesized, which exhibited potent in vitro and in vivo antiviral activities with low cytotoxicity.
In vitro anti-human immunodeficiency virus (HIV) activities of transition state mimetic HIV protease inhibitors containing allophenylnorstatine
TLDR
Two compounds, K NI-227 and KNI-272, which were highly potent against HIV protease with little inhibition of other aspartic proteases, showed the most potent activity against the infectivity and cytopathic effect of a wide spectrum of HIV strains.
Solution NMR evidence that the HIV-1 protease catalytic aspartyl groups have different ionization states in the complex formed with the asymmetric drug KNI-272.
TLDR
These findings provide not only the first experimental evidence regarding the distinct protonation states of Asp25/125 in HIV-1 protease/drug complexes, but also shed light on interactions responsible for inhibitor binding that should form the basis for improved drug designs.
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