Recent strategies in the development of new human cytomegalovirus inhibitors

Martı́nez, Ana; Castro, Ana; Gil, Carmen; Pérez, Concepción

doi:10.1002/med.1008

Cited by 26 publications

(16 citation statements)

References 124 publications

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“…Identifying and characterizing antiviral targets is critical for the development of new therapeutic agents to treat infections and diseases caused by this virus (7,17,23,40,44,75). One such target or potential set of targets to come from these efforts is the herpesvirus maturational protease (pPR, e.g., HCMV pUL80a) and its genetically related substrate proteins (Fig.…”

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confidence: 99%

Enzymatic Activities of Human Cytomegalovirus Maturational Protease Assemblin and Its Precursor (pPR, pUL80a): Maximal Activity of pPR Requires Self-Interaction through Its Scaffolding Domain

Brignole

Gibson

2007

J Virol

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Herpesviruses encode an essential, maturational serine protease whose catalytic domain, assemblin (28 kDa), is released by self-cleavage from a 74-kDa precursor (pPR, pUL80a). Although there is considerable information about the structure and enzymatic characteristics of assemblin, a potential pharmacologic target, comparatively little is known about these features of the precursor. To begin studying pPR, we introduced five point mutations that stabilize it against self-cleavage at its internal (I), cryptic (C), release (R), and maturational (M) sites and at a newly discovered "tail" (T) site. The resulting mutants, called ICRM-pPR and ICRMT-pPR, were expressed in bacteria, denatured in urea, purified by immobilized metal affinity chromatography, and renatured by a two-step dialysis procedure and by a new method of sedimentation into glycerol gradients. The enzymatic activities of the pPR mutants were indistinguishable from that of IC-assemblin prepared in parallel for comparison, as determined by using a fluorogenic peptide cleavage assay, and approximated rates previously reported for purified assemblin. The percentage of active enzyme in the preparations was also comparable, as determined by using a covalent-binding suicide substrate. An unexpected finding was that, in the absence of the kosmotrope Na 2 SO 4 , optimal activity of pPR requires interaction through its scaffolding domain. We conclude that although the enzymatic activities of assemblin and its precursor are comparable, there may be differences in how their catalytic sites become fully activated.Human cytomegalovirus (HCMV) is a ubiquitous, opportunistic pathogen of the herpesvirus family that causes lifethreatening illness in immunocompromised individuals (47,52,64). Identifying and characterizing antiviral targets is critical for the development of new therapeutic agents to treat infections and diseases caused by this virus (7,17,23,40,44,75). One such target or potential set of targets to come from these efforts is the herpesvirus maturational protease (pPR, e.g., HCMV pUL80a) and its genetically related substrate proteins (Fig. 1A), including the precursor assembly protein (pAP, pUL80.5) (36,37,77,78), which are essential for the production of infectious virus (19,24,58).Together, the UL80a proteins coordinate the process of capsid assembly and maturation to a form that is competent for DNA packaging (9, 25, 67). At the earliest stages of the process, pAP is required to translocate the major capsid protein (MCP; pUL86) into the nucleus and then to serve as an internal scaffold to direct its organization into the spherical procapsid shell (19,39,69,70,83). Once the procapsid is formed, the protease is required to sever pAP-MCP interactions, enabling elimination of the scaffolding proteins to make room for the viral DNA.The 28-kDa protease is incorporated into the scaffolding structure as a 74-kDa precursor that includes the entire pAP sequence as its carboxyl end (Fig. 1A) (60). This fusion sequence ensures protease targeting to the interior of...

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confidence: 99%

Enzymatic Activities of Human Cytomegalovirus Maturational Protease Assemblin and Its Precursor (pPR, pUL80a): Maximal Activity of pPR Requires Self-Interaction through Its Scaffolding Domain

Brignole

Gibson

2007

J Virol

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“…Such therapies include valganciclovir, the valyl ester of ganciclovir, and nonnucleoside inhibitors of CMV replication [26].…”

Section: Pharmacologic Treatmentmentioning

confidence: 99%

Congenital cytomegalovirus infection

Bale

Miner

Petheram

2002

Curr Treat Options Neurol

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Intrauterine infection with cytomegalovirus (CMV), a betaherpesvirus, remains the most frequent congenital virus infection in many regions of the world. Although most CMV-infected newborns lack signs of CMV infection, approximately 10% have signs that can consist of low birth weight, jaundice, hepatosplenomegaly, skin rash, microcephaly, and chorioretinitis. Neonates with signs of CMV infection at birth have high rates of audiologic and neurodevelopmental sequelae. Although postnatal therapy with ganciclovir transiently reduces virus shedding and may lessen the audiologic consequences of CMV in some infected infants, additional strategies are needed to prevent congenital CMV disease and to improve the neurodevelopmental prognosis of infants infected with CMV in utero. Some cases of intrauterine infections can be prevented in susceptible women by avoiding contact with the urine or saliva of young children who may be shedding CMV. Vaccines against CMV remain in the experimental stages of development. Termination of pregnancy can be offered to women whose infants have evidence of intrauterine CMV infection and sonographic signs of central nervous system damage. Infants who survive symptomatic intrauterine infections have high rates of neurodevelopmental sequelae and require comprehensive evaluation and therapy through center and home-based early intervention programs.

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“…Ganciclovir (and its prodrug valganciclovir), foscarnet, cidofovir and formivirsen ( Figures 1 and 2), the only drugs approved for treatment of HCMV infections, are less than ideal agents due to their significant toxicity, modest efficacy and poor drug delivery options [10,[15][16][17][18][19]. Clearly, improved alternatives are needed for treating herpesvirus infections in immunocompromised patients and the majority of recent antiviral research on herpesviruses has focused on HCMV [10,16,20,21].…”

Section: Introductionmentioning

confidence: 99%

Non‐nucleoside inhibitors of herpesviruses

Wathen¹

2002

Reviews in Medical Virology

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While the treatment of herpes simplex virus with acyclovir and similar nucleoside analogues was one of the first success stories in antiviral chemotherapy, substantial unmet medical needs remain for herpesvirus diseases. In particular, the increasing numbers of immunosuppressed people due to AIDS, transplantation, cancer and aging has driven the need for improved antivirals to treat diseases caused by human cytomegalovirus (HCMV). Currently available drugs for the treatment of HCMV diseases are less than ideal agents due to issues of toxicity, modest efficacy and poor oral bioavailability. High throughput screening of large compound collections for inhibitors of specific viral enzymes or inhibition of viral growth in cell culture have identified a number of new HCMV inhibitors at several pharmaceutical companies. These compounds act by inhibition of novel molecular targets such as the viral protein kinase, viral protease and viral proteins involved in DNA cleavage/packaging. In addition, novel non-nucleoside inhibitors of the herpesvirus DNA polymerase have recently been described. This review will summarise some of these research efforts and will focus on non-nucleoside compounds that directly inhibit a viral process.

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Recent strategies in the development of new human cytomegalovirus inhibitors

Cited by 26 publications

References 124 publications

Enzymatic Activities of Human Cytomegalovirus Maturational Protease Assemblin and Its Precursor (pPR, pUL80a): Maximal Activity of pPR Requires Self-Interaction through Its Scaffolding Domain

Enzymatic Activities of Human Cytomegalovirus Maturational Protease Assemblin and Its Precursor (pPR, pUL80a): Maximal Activity of pPR Requires Self-Interaction through Its Scaffolding Domain

Congenital cytomegalovirus infection

Non‐nucleoside inhibitors of herpesviruses

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