Toward a universal inhibitor of retroviral proteases: Comparative analysis of the interactions of LP‐130 complexed with proteases from HIV‐1, FIV, and EIAV

Kervinen, Jukka; Łubkowski, J.; Zdanov, Alexander; Bhatt, Deepa; Dunn, Ben M.; Hui, Kwan Y.; Powell, David J.; Kay, John; Wlodawer, Alexander; Gustchina, Alla

doi:10.1002/pro.5560071108

Cited by 33 publications

(36 citation statements)

References 37 publications

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“…It has been shown that inhibitors of the catalytic function or reactivity associated with a protein fold effective across species are not likely to elicit drug resistance by amino acid mutation (26). Thus, because dehydrons are highly conserved and promoters of interactions (3), it makes sense that ''universal inhibitors'' (i.e., those effective across species and not eliciting drug resistance) should be designed precisely to wrap such dehydrons.…”

Section: Discussionmentioning

confidence: 99%

Inhibitor design by wrapping packing defects in HIV-1 proteins

Fernández

Rogale

Scott

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

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Two viral proteins, HIV-1 protease and HIV-1 integrase, have been targeted for inhibitor design to prevent assembly and maturation of HIV-1 virions. The enzymatic mechanism of these proteins involves side-chain groups that serve as general acids or bases. Furthermore, catalytic activity requires that water be removed from the microenvironment surrounding the chemical reaction site or be constrained to serve as an activated nucleophile. Here, we identify previously unrecognized structural features that promote water removal from polar catalytic regions. Packing defects in the form of hydrogen bonds that are insufficiently dehydrated intramolecularly, named ''dehydrons,'' are strategically placed in the structure to induce an anhydrous enzymatic pathway. Dehydrons become electrostatically enhanced and stabilized upon further desolvation. Thus, packing defects act synergistically with the polar active groups to enhance the enzymatic electrostatics. However, because dehydrons are sticky, they constitute targets for inhibitor design. We noticed that inhibitors attach to polar surfaces by further desolvating dehydrons, thus blocking the active sites or the sites involved in harnessing the substrate. The dehydrons are thus required for functional reasons, making them suitable targets. The differences in success when targeting HIV-1 protease, feline immunodeficiency virus protease, and HIV-1 integrase are rationalized in terms of the dehydron distribution, revealing possible improvements in the targeting strategy. Principles of design optimization are proposed to create an inhibitor that can be neutralized only at the expense of the loss of catalytic function. The possibility of using drugs that wrap dehydrons to block proteinprotein associations is also discussed.

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Section: Discussionmentioning

confidence: 99%

Inhibitor design by wrapping packing defects in HIV-1 proteins

Fernández

Rogale

Scott

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

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“…The program allows the use of multiple template crystal structures as an input and can create multiple homologous models as an output. We used the highest-resolution (1.2-to 2.4-Å) crystal structures of HIV-1 (18), HIV-2 (33), EIAV (13), FIV (14), and RSV (47) 4 Å], respectively) and generated three simultaneous models for each protease. RSV protease structure was used to interpret the AMV protease results: AMV and RSV proteases differ in only two residues, which are not expected to be involved in the enzyme-substrate interactions (34).…”

Section: Retroviral Proteasesmentioning

confidence: 99%

Amino Acid Preferences for a Critical Substrate Binding Subsite of Retroviral Proteases in Type 1 Cleavage Sites

Bagossi

Sperka

Fehér

et al. 2005

J Virol

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The specificities of the proteases of 11 retroviruses representing each of the seven genera of the family Retroviridae were studied using a series of oligopeptides with amino acid substitutions in the P2 position of a naturally occurring type 1 cleavage site (Val-Ser-Gln-Asn-Tyr2Pro-Ile-Val-Gln; the arrow indicates the site of cleavage) in human immunodeficiency virus type 1 (HIV-1). This position was previously found to be one of the most critical in determining the substrate specificity differences of retroviral proteases. Specificities at this position were compared for HIV-1, HIV-2, equine infectious anemia virus, avian myeloblastosis virus, MasonPfizer monkey virus, mouse mammary tumor virus, Moloney murine leukemia virus, human T-cell leukemia virus type 1, bovine leukemia virus, human foamy virus, and walleye dermal sarcoma virus proteases. Three types of P2 preferences were observed: a subgroup of proteases preferred small hydrophobic side chains (Ala and Cys), and another subgroup preferred large hydrophobic residues (Ile and Leu), while the protease of HIV-1 preferred an Asn residue. The specificity distinctions among the proteases correlated well with the phylogenetic tree of retroviruses prepared solely based on the protease sequences. Molecular models for all of the proteases studied were built, and they were used to interpret the results. While size complementarities appear to be the main specificity-determining features of the S2 subsite of retroviral proteases, electrostatic contributions may play a role only in the case of HIV proteases. In most cases the P2 residues of naturally occurring type 1 cleavage site sequences of the studied proteases agreed well with the observed P2 preferences.

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“…Inhibitors of aspartic proteases have been designed for treatment of AIDS, hypertension, stroke, inflammation, asthma, osteoporosis, the common cold and arthritis [26,28,41,[60][61][62].…”

Section: Aspartic Protease Inhibitors In the Clinicmentioning

confidence: 99%

Proteases: Nature’s Destroyers and the Drugs that Stop Them

Veltri¹

2015

PPIJ

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Proteases are found in all life forms and regulate many cellular pathways. Proteases have been proven as viable drug targets. This paper reviews the mechanism of hydrolysis of the amino acid based aspartic, cysteine, serine and threonine proteases and will also highlight the current anti protease therapeutics in the clinic. the oxygen of the carbonyl drive the cleavage of the peptide bond, which abstracts hydrogen from the general base. Water then releases the second half of the product from the active site residue. The oxyanion hole generated during the transition state is stabilized through hydrogen bonding with amino groups of the backbone. The role of the oxyanion hole is not fully understood [18]. While the chemistry of the mechanism of hydrolysis is similar for serine, aspartic, cysteine and threonine proteases, the amino acids involved in catalysis are what define the various classes. The different classes of proteases are discussed below. Serine ProteasesSerine proteases [19][20][21] use an active site serine to hydrolyze a peptide bond. The other amino acids involved in catalysis vary between the different serine protease groups. The Ser-His-Asp triad can be replaced with Ser-His-Glu, Ser-His-His or Ser-Lys depending on the family of serine protease [20,21]. The serine proteases are categorized by tertiary structures into the super families of the trypsin-like or subtilisin-like [2,19,20]. Examples of the trypsin-like serine proteases, the larger of the super families, are trypsin, chymotrypsin, thrombin, factor IX a, and factor Xa [2,19,20]. Interestingly, some cysteine proteases adopt the trypsin-like structure [22]. Examples of the subtilisin-like serine proteases are proteinase K and thermitase [2,19,20]. Proteases: Nature's Destroyers and the Drugs that Stop Them 3/11Copyright: ©2015 Veltri Citation: Veltri CA (2015) Proteases: Nature's Destroyers and the Drugs that Stop Them. Pharm Pharmacol Int J 2(6): 00044. DOI: 10.15406/ ppij.2015.02.00044Along with tertiary structure, serine proteases are designed against the nature of the P 1 residue recognized by the protease types. The trypsin-like proteases cleave positively charged residues (Lys or Arg are preferred at P 1 ), elastase-like proteases prefer small hydrophobic residues (Ala or Val are preferred at P 1 ) while chymotrypsin-like proteases prefer large hydrophobic residues (Phe, Tyr, or Leu) [2,19,20]. Aspartic ProteasesAspartic proteases [19,[23][24][25][26] use two aspartic acid residues to hydrolyze a peptide bond. These proteases are categorized into the super families of pepsin-like or viral retropepsin-like due to the tertiary structure [23,24,26,27]. The pepsin-like include pepsin, cathepsin D and chymosin [23,27]. The viral retropepsinlike include the retro pepsins of the immune viruses HIV, FIV and SIV [24,26].Aspartic proteases are unique in the fact they do not have a His residue in their active site. The general acid-base mechanism proposed for peptide hydrolysis involves two Asp residues and uses water to attack the targe...

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Toward a universal inhibitor of retroviral proteases: Comparative analysis of the interactions of LP‐130 complexed with proteases from HIV‐1, FIV, and EIAV

Cited by 33 publications

References 37 publications

Inhibitor design by wrapping packing defects in HIV-1 proteins

Inhibitor design by wrapping packing defects in HIV-1 proteins

Amino Acid Preferences for a Critical Substrate Binding Subsite of Retroviral Proteases in Type 1 Cleavage Sites

Proteases: Nature’s Destroyers and the Drugs that Stop Them

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